rs139552940

chr21-46131981-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5 PP3 PP5

The NM_001849.4(COL6A2):c.2489G>A(p.Arg830Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000764 in 1,609,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R830W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 7.93

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 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-46131980-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287934.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799
• PP5: Variant 21-46131981-G-A is Pathogenic according to our data. Variant chr21-46131981-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210747.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr21-46131981-G-A is described in Lovd as [Pathogenic]. Variant chr21-46131981-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.2489G>A	p.Arg830Gln	missense_variant	28/28	ENST00000300527.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.2489G>A	p.Arg830Gln	missense_variant	28/28	1	NM_001849.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152214 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000590 AC: 14 AN: 237182 Hom.: 0 AF XY: 0.0000538 AC XY: 7 AN XY: 130104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.0000664

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000569

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000782 AC: 114 AN: 1456910 Hom.: 0 Cov.: 33 AF XY: 0.0000855 AC XY: 62 AN XY: 724808

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000897

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000931

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000828

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152332 Hom.: 0 Cov.: 34 AF XY: 0.0000805 AC XY: 6 AN XY: 74498

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000415 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 11, 2017	- -

Bethlem myopathy 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 830 of the COL6A2 protein (p.Arg830Gln). This variant is present in population databases (rs139552940, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive Bethlem myopathy (PMID: 29419890). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 210747). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg830 amino acid residue in COL6A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19884007, 31127727). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 07, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.61
Sift	Benign	0.14	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.85
MVP		0.73
MPC		0.65
ClinPred		0.38	T
GERP RS		4.2
Varity_R		0.20
gMVP		0.73

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: rs139552940; hg19: chr21-47551895; COSMIC: COSV52426139; COSMIC: COSV52426139;