rs768434256

chr21-46112032-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001849.4(COL6A2):c.169G>A(p.Val57Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,612,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.836

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]

LOC124905043 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16964623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.169G>A	p.Val57Ile	missense_variant	3/28	ENST00000300527.9
COL6A2	NM_058174.3	c.169G>A	p.Val57Ile	missense_variant	3/28	ENST00000397763.6
COL6A2	NM_058175.3	c.169G>A	p.Val57Ile	missense_variant	3/28
LOC124905043	XR_007067910.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.169G>A	p.Val57Ile	missense_variant	3/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.169G>A	p.Val57Ile	missense_variant	3/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.169G>A	p.Val57Ile	missense_variant	2/27	5
COL6A2	ENST00000436769.5	c.169G>A	p.Val57Ile	missense_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250696 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1460714 Hom.: 0 Cov.: 33 AF XY: 0.0000317 AC XY: 23 AN XY: 726666

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000574

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74292

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 25, 2020	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	17
Dann	Benign	0.94
DEOGEN2	Benign	0.20	T;.;T;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.87	D;D;T;.;D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.30	N;N;.;N;N
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.54	N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.19	T;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T
Polyphen		0.82	P;B;.;B;P
Vest4		0.13
MutPred		0.44		Loss of disorder (P = 0.1699);Loss of disorder (P = 0.1699);Loss of disorder (P = 0.1699);Loss of disorder (P = 0.1699);Loss of disorder (P = 0.1699);
MVP		0.51
MPC		0.11
ClinPred		0.034	T
GERP RS		1.4
Varity_R		0.080
gMVP		0.23

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: rs768434256; hg19: chr21-47531946; COSMIC: COSV55998741; COSMIC: COSV55998741;