rs149534094

Positions:

• chr21-46003792-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001848.3(COL6A1):​c.2866G>A​(p.Glu956Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00156 in 1,611,122 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (39 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.30

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008347839).
• BP6: Variant 21-46003792-G-A is Benign according to our data. Variant chr21-46003792-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00143 (218/152376) while in subpopulation SAS AF= 0.00683 (33/4834). AF 95% confidence interval is 0.005. There are 2 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.2866G>A	p.Glu956Lys	missense_variant	35/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.2866G>A	p.Glu956Lys	missense_variant	35/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152258 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00291 AC: 720 AN: 247078 Hom.: 12 AF XY: 0.00323 AC XY: 434 AN XY: 134502

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.0329

Gnomad EAS exome AF: 0.0000554

Gnomad SAS exome AF: 0.00921

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000613

Gnomad OTH exome AF: 0.00463

GnomAD4 exome AF: 0.00158 AC: 2300 AN: 1458746 Hom.: 39 Cov.: 34 AF XY: 0.00184 AC XY: 1337 AN XY: 725318

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.0367

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00884

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000284

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152376 Hom.: 2 Cov.: 34 AF XY: 0.00149 AC XY: 111 AN XY: 74522

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000522

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00683

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00359 Hom.: 7

Bravo AF: 0.00114

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00259 AC: 314

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2016	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)	Aug 19, 2015	- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

COL6A1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Uncertain	0.34
Sift	Benign	0.055	T;.
Sift4G	Benign	0.11	T;T
Polyphen		0.0080	B;.
Vest4		0.28
MVP		0.82
MPC		0.49
ClinPred		0.027	T
GERP RS		4.0
Varity_R		0.24
gMVP		0.50

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: rs149534094; hg19: chr21-47423706; COSMIC: COSV62614284; COSMIC: COSV62614284;