rs35881321

Positions:

• chr21-46112542-G-C
• chr21-46112542-G-A
• chr21-46112542-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001849.4(COL6A2):​c.679G>C​(p.Asp227His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D227N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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]

COL6A2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.679G>C	p.Asp227His	missense_variant	3/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.679G>C	p.Asp227His	missense_variant	3/28		NP_478054.2
COL6A2	NM_058175.3	c.679G>C	p.Asp227His	missense_variant	3/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.679G>C	p.Asp227His	missense_variant	3/28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.679G>C	p.Asp227His	missense_variant	3/28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.679G>C	p.Asp227His	missense_variant	2/27	5		ENSP00000387115.1
COL6A2	ENST00000460886.1	n.125G>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

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

Aug 04, 2023

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. ClinVar contains an entry for this variant (Variation ID: 476491). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 227 of the COL6A2 protein (p.Asp227His). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.27	T;.;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.80	T;T;.;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.79	N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		1.0	D;B;B;P
Vest4		0.61
MutPred		0.33		Loss of disorder (P = 0.1352);Loss of disorder (P = 0.1352);Loss of disorder (P = 0.1352);Loss of disorder (P = 0.1352);
MVP		0.86
MPC		0.23
ClinPred		0.52	D
GERP RS		3.2
Varity_R		0.18
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35881321; hg19: chr21-47532456;