rs61735835

Positions:

• chr21-46115902-G-A

Variant summary

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

The NM_001849.4(COL6A2):​c.832G>A​(p.Glu278Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,612,902 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (18 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.80

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 -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_001849.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.008608341).
• BP6: Variant 21-46115902-G-A is Benign according to our data. Variant chr21-46115902-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46115902-G-A is described in Lovd as [Benign]. Variant chr21-46115902-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00923 (1406/152272) while in subpopulation AFR AF= 0.0306 (1272/41558). AF 95% confidence interval is 0.0292. There are 21 homozygotes in gnomad4. There are 685 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.832G>A	p.Glu278Lys	missense_variant	6/28	ENST00000300527.9
COL6A2	NM_058174.3	c.832G>A	p.Glu278Lys	missense_variant	6/28	ENST00000397763.6
COL6A2	NM_058175.3	c.832G>A	p.Glu278Lys	missense_variant	6/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.832G>A	p.Glu278Lys	missense_variant	6/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.832G>A	p.Glu278Lys	missense_variant	6/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.832G>A	p.Glu278Lys	missense_variant	5/27	5
COL6A2	ENST00000485591.1	n.488G>A		non_coding_transcript_exon_variant	2/7	3

Frequencies

GnomAD3 genomes AF: 0.00921 AC: 1401 AN: 152154 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00228 AC: 569 AN: 249318 Hom.: 7 AF XY: 0.00168 AC XY: 227 AN XY: 135280

Gnomad AFR exome AF: 0.0312

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000948 AC: 1385 AN: 1460630 Hom.: 18 Cov.: 33 AF XY: 0.000824 AC XY: 599 AN XY: 726608

Gnomad4 AFR exome AF: 0.0330

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00923 AC: 1406 AN: 152272 Hom.: 21 Cov.: 32 AF XY: 0.00920 AC XY: 685 AN XY: 74458

Gnomad4 AFR AF: 0.0306

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00230 Hom.: 10

Bravo AF: 0.0106

ESP6500AA AF: 0.0239 AC: 105

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00252 AC: 306

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 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. -

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 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.94	D;T;.;D
MetaRNN	Benign	0.0086	T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.2	L;L;L;L
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.99	N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.90	P;P;P;P
Vest4		0.54
MVP		0.97
MPC		0.55
ClinPred		0.016	T
GERP RS		4.0
Varity_R		0.27
gMVP		0.51

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: rs61735835; hg19: chr21-47535816;