rs747900252

Variant names:

• chr21-46125776-G-A
• rs747900252
• NM_001849.4:c.1970-9G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46125776-G-A
• chr21-46125776-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_001849.4(COL6A2):​c.1970-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000714 in 1,610,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Scores: Splicing: ADA: 0.9941
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:2
• Conservation: PhyloP100: -1.44
• Publications: 7 publications found

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

COL6A2 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 21-46125776-G-A is Pathogenic according to our data. Variant chr21-46125776-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1970-9G>A		intron_variant	Intron 25 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1970-9G>A		intron_variant	Intron 25 of 27	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1970-9G>A		intron_variant	Intron 25 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1970-9G>A		intron_variant	Intron 25 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1970-9G>A		intron_variant	Intron 25 of 27	5	NM_058174.3	ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1970-9G>A		intron_variant	Intron 24 of 26	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.641-9G>A		intron_variant	Intron 10 of 10	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000109 AC: 27 AN: 247562 AF XY: 0.0000816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000713 AC: 104 AN: 1458730 Hom.: 0 Cov.: 36 AF XY: 0.0000744 AC XY: 54 AN XY: 725340

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.000470 AC: 21 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52106

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000657 AC: 73 AN: 1110484

Other (OTH) AF: 0.000149 AC: 9 AN: 60284

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74362

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.000458 AC: 7 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000174

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Jul 10, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 14, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies show this variant affects the deposition and organization of collagen VI in the extracellular matrix, and the collagen VI level is decreased (PMID: 19309692); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 21280092, 20882040, 28578317, 25535305, 27447704, 34426522, 19309692, 20576434, 20976770, 29774307, 30609409, 32065942, 32363432, 31127727, 34106991, 37526466, 33441455, 38374194, 37569848, 33250842, 38155714, 24314752)

Jan 20, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 21, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 10, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bethlem myopathy 1A Pathogenic:2

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 25 of the COL6A2 gene. It does not directly change the encoded amino acid sequence of the COL6A2 protein. This variant is present in population databases (rs747900252, gnomAD 0.04%). This variant has been observed in individual(s) with autosomal recessive COL6A2-related conditions (PMID: 19309692, 20576434, 21280092, 25535305; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265506). Studies have shown that this variant alters COL6A2 gene expression (PMID: 19309692). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Ullrich congenital muscular dystrophy 1A Pathogenic:2

May 04, 2022

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous c.1970-9G>A variant in COL6A2 was identified by our study, along with a variant of uncertain significance, in 2 unrelated individuals with either Bethlem myopathy 1 or Ullrich congenital muscular dystrophy 1. The variant has been reported in at least 11 individuals of Brazilian, European, and unknown ethnicity with Ullrich congenital muscular dystrophy 1 or Bethlem myopathy 1 (PMID: 27447704, 19309692, 28578317, 32065942, 21280092, 20576434, 25535305, 20976770, 24314752), and has been identified in 0.04% (15/35314) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs747900252). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 265506) as pathogenic by multiple submitters, as likely pathogenic by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, and as likely benign by Illumina Clinical Services Laboratory. In vitro functional studies provide some evidence that the c.1970-9G>A variant may impact protein function (PMID: 19309692, 21280092). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in at least 3 affected homozygotes, in combination with reported likely pathogenic variants, in combination with reported variants of uncertain significance, and in at least 11 individuals with Ullrich congenital muscular dystrophy 1 or Bethlem myopathy 1 increases the likelihood that the c.1970-9G>A variant is pathogenic (VariationID: 497233; PMID: 19309692, 28578317, 32065942, 21280092, 20576434, 25535305, 20976770, 24314752). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PS3_moderate, PP3 (Richards 2015).

Aug 05, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Predicted Consequence/Location: Intron variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19309692, 21280092).In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.85 (>=0.2, moderate evidence for spliceogenicity)]. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21280092, 25535305). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000265506 /PMID: 19309692). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Congenital hip dislocation;C0085639:Falls;C0151786:Muscle weakness;C0311394:Difficulty walking;C3279725:Hip flexor weakness Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Collagen 6-related myopathy Pathogenic:1

May 03, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL6A2 c.1970-9G>A splice region variant has been reported in at least six studies in which it was found in a total of seven affected individuals, including in one in a homozygous state, in five in a compound heterozygous state with a truncating variant on the second allele, and in one in a heterozygous state in whom the second allele was not detected. The individuals were affected with a range of phenotypes from a moderately severe form of Ullrich congenital muscular dystrophy through different intermediate phenotypes to a milder Bethlem myopathy (Martoni et al. 2009; Deconinck et al. 2010; Foley et al. 2011; Quijano-Roy et al. 2014; Deconinck et al. 2015; Stehlíková et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000436 in the Latino population of the Genome Aggregation Database. The c.1970-9G>A variant was shown to create a cryptic splice site in intron 25, leading to a frameshift and premature termination of the protein and reduced transcript levels to 20% of normal (Martoni et al. 2009). RT-PCR experiments in patient fibroblasts showed the presence of some normally spliced transcript (Foley e al. 2011). Studies in patient fibroblast cultures demonstrated that the variant resulted in significantly reduced levels of collagen VI protein, decreased intracellular secretion, and abnormal deposition and organization of the protein in the extracellular matrix (Martoni et al. 2009; Deconinck et al. 2015). Based on the collective evidence, the c.1970-9G>A variant is classified as pathogenic for an autosomal recessive form of collagen type VI-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Abnormality of the musculature Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Qualitative or quantitative defects of collagen 6 Pathogenic:1

Jun 07, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1970-9G>A variant in COL6A2 has been reported in 3 individuals (two compou nd heterozygotes who had other disease-causing variants in trans and one homozyg ote) with Ullrich congenital muscular dystrophy (Martoni 2009, Foley 2011, Decon ninck 2014). This variant has also been identified in 7/113354 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s747900252). This frequency is low enough to be consistent with a recessive carr ier frequency. The c.1970-9G>A variant was demonstrated to cause altered splici ng, leading to a frameshift and a truncated or absent protein (Martoni 2009, Fol ey 2011). In summary, this variant meets our criteria to be classified as patho genic for collagen VI-related myopathy in an autosomal recessive manner based up on its segregation in affected individuals, low frequency in controls and functi onal impact.

Bethlem myopathy Uncertain:1

Oct 19, 2020

Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

28-year-old female, born as a floppy baby with some improvement. At the moment, she has proximal and distal weakness, and myogenic electromyography.

Ullrich congenital muscular dystrophy 1B Uncertain:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	22
DANN	Benign	0.79
PhyloP100		-1.4
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.85		Position offset: 2
DS_AL_spliceai		0.45		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs747900252; hg19: chr21-47545690;