rs77632596

Positions:

• chr2-237366926-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004369.4(COL6A3):​c.5261A>G​(p.Lys1754Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00868 in 1,614,222 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (63 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.293

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a domain VWFA 9 (size 173) in uniprot entity CO6A3_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_004369.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.008732289).
• BP6: Variant 2-237366926-T-C is Benign according to our data. Variant chr2-237366926-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 94945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237366926-T-C is described in Lovd as [Benign]. Variant chr2-237366926-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0079 (1203/152336) while in subpopulation AMR AF= 0.00987 (151/15300). AF 95% confidence interval is 0.00896. There are 17 homozygotes in gnomad4. There are 616 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.5261A>G	p.Lys1754Arg	missense_variant	11/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.4643A>G	p.Lys1548Arg	missense_variant	10/43		NP_476508.2
COL6A3	NM_057166.5	c.3440A>G	p.Lys1147Arg	missense_variant	8/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.5261A>G	p.Lys1754Arg	missense_variant	11/44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.3440A>G	p.Lys1147Arg	missense_variant	8/41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.4643A>G	p.Lys1548Arg	missense_variant	10/43	5		ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 1204 AN: 152218 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00957

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00775 AC: 1949 AN: 251478 Hom.: 9 AF XY: 0.00784 AC XY: 1065 AN XY: 135914

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00876 AC: 12802 AN: 1461886 Hom.: 63 Cov.: 32 AF XY: 0.00858 AC XY: 6240 AN XY: 727242

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00528

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.00964

Gnomad4 OTH exome AF: 0.00859

GnomAD4 genome AF: 0.00790 AC: 1203 AN: 152336 Hom.: 17 Cov.: 33 AF XY: 0.00827 AC XY: 616 AN XY: 74500

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.00957

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00994 Hom.: 12

Bravo AF: 0.00760

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00775 AC: 941

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 02, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 0.77% in ExAC, 1.1% in European population with 4 homozygotes. Emory, GeneDx, and CHOP report as B/LB -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	COL6A3: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Bethlem myopathy 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T;.;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.77	T;T;T;T;.
MetaRNN	Benign	0.0087	T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.17	.;N;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.72	N;N;N;.;N
REVEL	Benign	0.23
Sift	Benign	0.22	T;T;T;.;T
Sift4G	Benign	0.37	T;T;T;T;T
Polyphen		0.78	P;B;.;.;P
Vest4		0.20
MVP		0.77
MPC		0.18
ClinPred		0.0035	T
GERP RS		1.8
Varity_R		0.16
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77632596; hg19: chr2-238275569;