rs17357592

Variant names:

• chr21-46122865-C-T
• rs17357592
• NM_001849.4:c.1609-10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001849.4(COL6A2):​c.1609-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,611,276 control chromosomes in the GnomAD database, including 24,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1363 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22827 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Scores: Splicing: ADA: 0.00001742
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.833
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-46122865-C-T is Benign according to our data. Variant chr21-46122865-C-T is described in ClinVar as [Benign]. Clinvar id is 93913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1609-10C>T		intron_variant	Intron 20 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1609-10C>T		intron_variant	Intron 20 of 27		NP_478054.2
COL6A2	NM_058175.3	c.1609-10C>T		intron_variant	Intron 20 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1609-10C>T		intron_variant	Intron 20 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1609-10C>T		intron_variant	Intron 20 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1609-10C>T		intron_variant	Intron 19 of 26	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.232-10C>T		intron_variant	Intron 5 of 10	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17889 AN: 152088 Hom.: 1365 Cov.: 32

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.0752

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.121 AC: 30183 AN: 250224 AF XY: 0.124

Gnomad AFR exome AF: 0.0490

Gnomad AMR exome AF: 0.0693

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.0246

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.167 AC: 243740 AN: 1459070 Hom.: 22827 Cov.: 33 AF XY: 0.165 AC XY: 119433 AN XY: 725920

African (AFR) AF: 0.0428 AC: 1431 AN: 33468

American (AMR) AF: 0.0731 AC: 3267 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 4121 AN: 26122

East Asian (EAS) AF: 0.0225 AC: 892 AN: 39698

South Asian (SAS) AF: 0.0778 AC: 6708 AN: 86220

European-Finnish (FIN) AF: 0.0678 AC: 3568 AN: 52616

Middle Eastern (MID) AF: 0.156 AC: 898 AN: 5764

European-Non Finnish (NFE) AF: 0.192 AC: 213468 AN: 1110160

Other (OTH) AF: 0.156 AC: 9387 AN: 60312

GnomAD4 genome AF: 0.118 AC: 17891 AN: 152206 Hom.: 1363 Cov.: 32 AF XY: 0.111 AC XY: 8259 AN XY: 74424

African (AFR) AF: 0.0495 AC: 2058 AN: 41540

American (AMR) AF: 0.0932 AC: 1425 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3470

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5170

South Asian (SAS) AF: 0.0746 AC: 360 AN: 4826

European-Finnish (FIN) AF: 0.0612 AC: 649 AN: 10610

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12403 AN: 67984

Other (OTH) AF: 0.128 AC: 269 AN: 2108

Alfa AF: 0.163 Hom.: 8697

Bravo AF: 0.118

Asia WGS AF: 0.0640 AC: 225 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 12, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Myosclerosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Collagen 6-related myopathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bethlem myopathy 1A Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.60
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17357592; hg19: chr21-47542779;