21-46119876-A-G

Variant names:

• chr21-46119876-A-G
• rs3737362
• NM_001849.4:c.1332+26A>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.1332+26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 1,550,732 control chromosomes in the GnomAD database, including 523,364 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51101 hom., cov: 32)
  • Exomes 𝑓: 0.82 (472263 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.972
• Publications: 10 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=-0.94).
• BP6: Variant 21-46119876-A-G is Benign according to our data. Variant chr21-46119876-A-G is described in ClinVar as Benign. ClinVar VariationId is 93905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1332+26A>G		intron_variant	Intron 15 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1332+26A>G		intron_variant	Intron 15 of 27		NP_478054.2
COL6A2	NM_058175.3	c.1332+26A>G		intron_variant	Intron 15 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1332+26A>G		intron_variant	Intron 15 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1332+26A>G		intron_variant	Intron 15 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1332+26A>G		intron_variant	Intron 14 of 26	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.819 AC: 124382 AN: 151894 Hom.: 51040 Cov.: 32

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.879

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.887

Gnomad SAS AF: 0.671

Gnomad FIN AF: 0.798

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.842

GnomAD2 exomes AF: 0.811 AC: 128153 AN: 158014 AF XY: 0.799

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.904

Gnomad ASJ exome AF: 0.783

Gnomad EAS exome AF: 0.867

Gnomad FIN exome AF: 0.807

Gnomad NFE exome AF: 0.823

Gnomad OTH exome AF: 0.827

GnomAD4 exome AF: 0.820 AC: 1147313 AN: 1398720 Hom.: 472263 Cov.: 35 AF XY: 0.815 AC XY: 562459 AN XY: 690130

African (AFR) AF: 0.793 AC: 25298 AN: 31918

American (AMR) AF: 0.904 AC: 32335 AN: 35774

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 20018 AN: 25156

East Asian (EAS) AF: 0.916 AC: 33194 AN: 36254

South Asian (SAS) AF: 0.661 AC: 52502 AN: 79374

European-Finnish (FIN) AF: 0.804 AC: 38774 AN: 48198

Middle Eastern (MID) AF: 0.781 AC: 4445 AN: 5690

European-Non Finnish (NFE) AF: 0.828 AC: 893417 AN: 1078382

Other (OTH) AF: 0.816 AC: 47330 AN: 57974

GnomAD4 genome AF: 0.819 AC: 124500 AN: 152012 Hom.: 51101 Cov.: 32 AF XY: 0.817 AC XY: 60723 AN XY: 74294

African (AFR) AF: 0.799 AC: 33100 AN: 41442

American (AMR) AF: 0.880 AC: 13444 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 2747 AN: 3470

East Asian (EAS) AF: 0.888 AC: 4573 AN: 5152

South Asian (SAS) AF: 0.670 AC: 3229 AN: 4822

European-Finnish (FIN) AF: 0.798 AC: 8473 AN: 10612

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.827 AC: 56164 AN: 67914

Other (OTH) AF: 0.842 AC: 1779 AN: 2112

Alfa AF: 0.815 Hom.: 9680

Bravo AF: 0.828

Asia WGS AF: 0.800 AC: 2782 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 16, 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

- -

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	-0.94
CADD	Benign	0.063
DANN	Benign	0.34
PhyloP100		-0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3737362; hg19: chr21-47539790; COSMIC: COSV56012319; COSMIC: COSV56012319;