chr21-46117915-G-T

Position:

• chr21-46117915-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001849.4(COL6A2):​c.1095G>T​(p.Glu365Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.691

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1095G>T	p.Glu365Asp	missense_variant	12/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1095G>T	p.Glu365Asp	missense_variant	12/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1095G>T	p.Glu365Asp	missense_variant	12/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1095G>T	p.Glu365Asp	missense_variant	12/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1095G>T	p.Glu365Asp	missense_variant	12/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.1095G>T	p.Glu365Asp	missense_variant	11/27	5		ENSP00000387115

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248166 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134652

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460700 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726632

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000416

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2023

This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 365 of the COL6A2 protein (p.Glu365Asp). ClinVar contains an entry for this variant (Variation ID: 542963). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL6A2 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.92	D;D;.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	-0.18	N;N;N;N
MutationTaster	Benign	0.91	D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.51	T;T;T;T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.79	P;D;D;P
Vest4		0.57
MutPred		0.32		Loss of methylation at R366 (P = 0.1579);Loss of methylation at R366 (P = 0.1579);Loss of methylation at R366 (P = 0.1579);Loss of methylation at R366 (P = 0.1579);
MVP		0.96
MPC		0.56
ClinPred		0.46	T
GERP RS		2.6
Varity_R		0.15
gMVP		0.16

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: rs374673302; hg19: chr21-47537829;