rs115957676

Positions:

• chr21-46112362-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001849.4(COL6A2):​c.499G>A​(p.Gly167Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000558 in 1,608,264 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G167C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (5 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.62

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009836435).
• BP6: Variant 21-46112362-G-A is Benign according to our data. Variant chr21-46112362-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.499G>A	p.Gly167Ser	missense_variant	3/28	ENST00000300527.9
COL6A2	NM_058174.3	c.499G>A	p.Gly167Ser	missense_variant	3/28	ENST00000397763.6
COL6A2	NM_058175.3	c.499G>A	p.Gly167Ser	missense_variant	3/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.499G>A	p.Gly167Ser	missense_variant	3/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.499G>A	p.Gly167Ser	missense_variant	3/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.499G>A	p.Gly167Ser	missense_variant	2/27	5
COL6A2	ENST00000436769.5	c.499G>A	p.Gly167Ser	missense_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 419 AN: 152056 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000714 AC: 168 AN: 235134 Hom.: 3 AF XY: 0.000532 AC XY: 69 AN XY: 129766

Gnomad AFR exome AF: 0.00969

Gnomad AMR exome AF: 0.000323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000454

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000670

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000329 AC: 479 AN: 1456090 Hom.: 5 Cov.: 33 AF XY: 0.000308 AC XY: 223 AN XY: 724080

Gnomad4 AFR exome AF: 0.00881

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.000221

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000649

Gnomad4 OTH exome AF: 0.000549

GnomAD4 genome AF: 0.00275 AC: 419 AN: 152174 Hom.: 1 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74404

Gnomad4 AFR AF: 0.00971

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.00288

ESP6500AA AF: 0.00657 AC: 28

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000939 AC: 112

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2015	- -

Myosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

COL6A2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;T;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;.;D
MetaRNN	Benign	0.0098	T;T;T;T;T
MetaSVM	Uncertain	0.075	D
MutationAssessor	Uncertain	2.3	M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.045	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.57
MVP		0.91
MPC		0.55
ClinPred		0.015	T
GERP RS		4.3
Varity_R		0.37
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs115957676; hg19: chr21-47532276;