rs398123650

Positions:

• chr21-46132253-G-A
• chr21-46132253-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001849.4(COL6A2):​c.2761G>A​(p.Val921Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000785 in 1,605,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V921L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 3.06

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06622955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.2761G>A	p.Val921Met	missense_variant	28/28	ENST00000300527.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.2761G>A	p.Val921Met	missense_variant	28/28	1	NM_001849.4	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152222 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000603

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000897 AC: 21 AN: 234188 Hom.: 0 AF XY: 0.0000624 AC XY: 8 AN XY: 128304

Gnomad AFR exome AF: 0.000894

Gnomad AMR exome AF: 0.0000297

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: 0.0000660

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000654 AC: 95 AN: 1453182 Hom.: 0 Cov.: 35 AF XY: 0.0000609 AC XY: 44 AN XY: 722960

Gnomad4 AFR exome AF: 0.000570

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.0000205

Gnomad4 NFE exome AF: 0.0000586

Gnomad4 OTH exome AF: 0.0000831

GnomAD4 genome AF: 0.000203 AC: 31 AN: 152340 Hom.: 0 Cov.: 34 AF XY: 0.000175 AC XY: 13 AN XY: 74486

Gnomad4 AFR AF: 0.000601

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: 0.0000882

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000204

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 03, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 01, 2022	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.2761G>A (p.V921M) alteration is located in exon 28 (coding exon 27) of the COL6A2 gene. This alteration results from a G to A substitution at nucleotide position 2761, causing the valine (V) at amino acid position 921 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.58	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.92	P
Vest4		0.34
MVP		0.72
MPC		0.42
ClinPred		0.073	T
GERP RS		-1.3
Varity_R		0.067
gMVP		0.66

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: rs398123650; hg19: chr21-47552167; COSMIC: COSV52424508; COSMIC: COSV52424508;