chr21-46125241-A-G

Variant names:

• chr21-46125241-A-G
• rs2839113
• NM_001849.4:c.1771-25A>G

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.1771-25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 1,608,110 control chromosomes in the GnomAD database, including 528,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.81 (49786 hom., cov: 33)
  • Exomes 𝑓: 0.81 (478986 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.607
• Publications: 12 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-46125241-A-G is Benign according to our data. Variant chr21-46125241-A-G is described in ClinVar as Benign. ClinVar VariationId is 93922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1771-25A>G		intron_variant	Intron 23 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1771-25A>G		intron_variant	Intron 23 of 27	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1771-25A>G		intron_variant	Intron 23 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1771-25A>G		intron_variant	Intron 23 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1771-25A>G		intron_variant	Intron 23 of 27	5	NM_058174.3	ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1771-25A>G		intron_variant	Intron 22 of 26	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.394-25A>G		intron_variant	Intron 8 of 10	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122787 AN: 152032 Hom.: 49733 Cov.: 33

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.835

GnomAD2 exomes AF: 0.803 AC: 199929 AN: 248836 AF XY: 0.792

Gnomad AFR exome AF: 0.786

Gnomad AMR exome AF: 0.903

Gnomad ASJ exome AF: 0.790

Gnomad EAS exome AF: 0.869

Gnomad FIN exome AF: 0.793

Gnomad NFE exome AF: 0.813

Gnomad OTH exome AF: 0.809

GnomAD4 exome AF: 0.809 AC: 1178158 AN: 1455960 Hom.: 478986 Cov.: 39 AF XY: 0.803 AC XY: 581636 AN XY: 724320

African (AFR) AF: 0.780 AC: 26077 AN: 33426

American (AMR) AF: 0.902 AC: 40166 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 20739 AN: 26002

East Asian (EAS) AF: 0.912 AC: 36187 AN: 39670

South Asian (SAS) AF: 0.631 AC: 54196 AN: 85926

European-Finnish (FIN) AF: 0.793 AC: 41371 AN: 52154

Middle Eastern (MID) AF: 0.775 AC: 4463 AN: 5756

European-Non Finnish (NFE) AF: 0.818 AC: 906504 AN: 1108334

Other (OTH) AF: 0.805 AC: 48455 AN: 60160

GnomAD4 genome AF: 0.808 AC: 122899 AN: 152150 Hom.: 49786 Cov.: 33 AF XY: 0.806 AC XY: 59909 AN XY: 74368

African (AFR) AF: 0.783 AC: 32494 AN: 41508

American (AMR) AF: 0.872 AC: 13344 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 2762 AN: 3472

East Asian (EAS) AF: 0.883 AC: 4556 AN: 5158

South Asian (SAS) AF: 0.641 AC: 3089 AN: 4818

European-Finnish (FIN) AF: 0.788 AC: 8344 AN: 10594

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.817 AC: 55562 AN: 67982

Other (OTH) AF: 0.836 AC: 1766 AN: 2112

Alfa AF: 0.815 Hom.: 63332

Bravo AF: 0.818

Asia WGS AF: 0.786 AC: 2732 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 16, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

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.

Myosclerosis Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bethlem myopathy 1A Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ullrich congenital muscular dystrophy 1A Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.1
DANN	Benign	0.72
PhyloP100		-0.61
La Branchor		0.58
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2839113; hg19: chr21-47545155;