rs727502832

chr21-46116387-G-Tchr21-46116387-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001849.4(COL6A2):c.911G>T(p.Gly304Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.08

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_001849.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 21-46116387-G-T is Pathogenic according to our data. Variant chr21-46116387-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162541.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.911G>T	p.Gly304Val	missense_variant	8/28	ENST00000300527.9
COL6A2	NM_058174.3	c.911G>T	p.Gly304Val	missense_variant	8/28	ENST00000397763.6
COL6A2	NM_058175.3	c.911G>T	p.Gly304Val	missense_variant	8/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.911G>T	p.Gly304Val	missense_variant	8/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.911G>T	p.Gly304Val	missense_variant	8/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.911G>T	p.Gly304Val	missense_variant	7/27	5
COL6A2	ENST00000485591.1	n.567G>T		non_coding_transcript_exon_variant	4/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 02, 2017

In summary, this variant is a rare missense change that resides within the COL6A2 triple helix region. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL6A2-related disease. This sequence change replaces glycine with valine at codon 304 of the COL6A2 protein (p.Gly304Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. Glycine residues within the triple helix region are crucial to maintain fibrillar collagens structure and stability (PMID: 7695699, 19344236). In the case of COL6A2, missense substitutions that affect glycine residues within the triplex helix domain have been reported in many patients affected with autosomal dominant collagen VI myopathy (PMID: 24038877). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	31
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.3	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.82
MutPred		0.81		Loss of relative solvent accessibility (P = 0.0306);Loss of relative solvent accessibility (P = 0.0306);Loss of relative solvent accessibility (P = 0.0306);Loss of relative solvent accessibility (P = 0.0306);
MVP		0.99
MPC		0.68
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.97
gMVP		1.0

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: rs727502832; hg19: chr21-47536301;