rs786205642

Positions:

• chr21-46125812-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The ENST00000300527.9(COL6A2):​c.1997G>A​(p.Ser666Asn) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S666R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 ENST00000300527.9 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 9.75

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 21-46125812-G-A is Pathogenic according to our data. Variant chr21-46125812-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1997G>A	p.Ser666Asn	missense_variant	26/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1997G>A	p.Ser666Asn	missense_variant	26/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1997G>A	p.Ser666Asn	missense_variant	26/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1997G>A	p.Ser666Asn	missense_variant	26/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1997G>A	p.Ser666Asn	missense_variant	26/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.1997G>A	p.Ser666Asn	missense_variant	25/27	5		ENSP00000387115
COL6A2	ENST00000413758.1	c.668G>A	p.Ser223Asn	missense_variant	11/11	3		ENSP00000395751

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -
Uncertain significance, flagged submission	clinical testing	Revvity Omics, Revvity	Dec 23, 2021	- -

Bethlem myopathy 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

This missense change has been observed in individual(s) with Bethlem myopathy (PMID: 18378883, 25211533). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 666 of the COL6A2 protein (p.Ser666Asn). ClinVar contains an entry for this variant (Variation ID: 191318). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 expected to disrupt COL6A2 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;.;.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.7	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.80
MutPred		0.82		Gain of catalytic residue at S666 (P = 0.0914);Gain of catalytic residue at S666 (P = 0.0914);Gain of catalytic residue at S666 (P = 0.0914);Gain of catalytic residue at S666 (P = 0.0914);.;
MVP		0.88
MPC		0.59
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.91
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs786205642; hg19: chr21-47545726;