rs141703710

chr21-46112179-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.316G>A(p.Glu106Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,612,984 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (119 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.48

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=0.009793192).
• BP6: Variant 21-46112179-G-A is Benign according to our data. Variant chr21-46112179-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46112179-G-A is described in Lovd as [Pathogenic]. Variant chr21-46112179-G-A is described in Lovd as [Benign]. Variant chr21-46112179-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.316G>A	p.Glu106Lys	missense_variant	3/28	ENST00000300527.9
COL6A2	NM_058174.3	c.316G>A	p.Glu106Lys	missense_variant	3/28	ENST00000397763.6
COL6A2	NM_058175.3	c.316G>A	p.Glu106Lys	missense_variant	3/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.316G>A	p.Glu106Lys	missense_variant	3/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.316G>A	p.Glu106Lys	missense_variant	3/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.316G>A	p.Glu106Lys	missense_variant	2/27	5
COL6A2	ENST00000436769.5	c.316G>A	p.Glu106Lys	missense_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 1044 AN: 152194 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00665 AC: 1666 AN: 250404 Hom.: 11 AF XY: 0.00688 AC XY: 934 AN XY: 135668

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00592

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.00621

GnomAD4 exome AF: 0.0118 AC: 17177 AN: 1460672 Hom.: 119 Cov.: 33 AF XY: 0.0114 AC XY: 8261 AN XY: 726630

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00496

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.00821

GnomAD4 genome AF: 0.00685 AC: 1044 AN: 152312 Hom.: 9 Cov.: 32 AF XY: 0.00622 AC XY: 463 AN XY: 74468

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.0110 Hom.: 14

Bravo AF: 0.00697

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0105 AC: 90

ExAC AF: 0.00706 AC: 857

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0115

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 06, 2015	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	COL6A2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 06, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Bethlem myopathy 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Collagen 6-related myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Ullrich congenital muscular dystrophy 1A;C1850671:Myosclerosis;CN029274:Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;T;.;.
Eigen	Benign	-0.018
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T;T;T;.;T
MetaRNN	Benign	0.0098	T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.1	L;L;.;L;L
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.49	T;T;T;T;T
Sift4G	Benign	0.84	T;T;T;T;T
Polyphen		0.83	P;B;.;B;B
Vest4		0.70
MVP		0.73
MPC		0.15
ClinPred		0.016	T
GERP RS		4.3
Varity_R		0.19
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs141703710; hg19: chr21-47532093;