rs61735828

Positions:

• chr21-46121563-G-C
• chr21-46121563-G-A

Variant summary

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

The NM_001849.4(COL6A2):​c.1466G>C​(p.Arg489Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,512 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R489Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63

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 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.1466G>C	p.Arg489Pro	missense_variant	18/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1466G>C	p.Arg489Pro	missense_variant	18/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1466G>C	p.Arg489Pro	missense_variant	18/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1466G>C	p.Arg489Pro	missense_variant	18/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1466G>C	p.Arg489Pro	missense_variant	18/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.1466G>C	p.Arg489Pro	missense_variant	17/27	5		ENSP00000387115
COL6A2	ENST00000413758.1	c.89G>C	p.Arg30Pro	missense_variant	3/11	3		ENSP00000395751

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460512 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726562

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 26, 2022

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 489 of the COL6A2 protein (p.Arg489Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 542990). 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. 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	0.22
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;.;.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T;T;.;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.18	N;N;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.97	N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.31	T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		1.0	D;D;D;D;.
Vest4		0.75
MutPred		0.29		Loss of methylation at R489 (P = 0.0134);Loss of methylation at R489 (P = 0.0134);Loss of methylation at R489 (P = 0.0134);Loss of methylation at R489 (P = 0.0134);.;
MVP		0.97
MPC		0.20
ClinPred		0.91	D
GERP RS		4.2
Varity_R		0.30
gMVP		0.51

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: rs61735828; hg19: chr21-47541477;