rs1555871311

chr21-46112030-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001849.4(COL6A2):c.167G>A(p.Ser56Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,688 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S56S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.72

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]

LOC124905043 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.167G>A	p.Ser56Asn	missense_variant	3/28	ENST00000300527.9
COL6A2	NM_058174.3	c.167G>A	p.Ser56Asn	missense_variant	3/28	ENST00000397763.6
LOC124905043	XR_007067910.1	n.2C>T		non_coding_transcript_exon_variant	1/2
COL6A2	NM_058175.3	c.167G>A	p.Ser56Asn	missense_variant	3/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.167G>A	p.Ser56Asn	missense_variant	3/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.167G>A	p.Ser56Asn	missense_variant	3/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.167G>A	p.Ser56Asn	missense_variant	2/27	5
COL6A2	ENST00000436769.5	c.167G>A	p.Ser56Asn	missense_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460688 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726662

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2023

This missense change has been observed in individual(s) with clinical features of autosomal dominant Bethlem myopathy (PMID: 34167565; Invitae). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 56 of the COL6A2 protein (p.Ser56Asn). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 476458). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 06, 2017

- -

Ullrich congenital muscular dystrophy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.167G>Ap.Ser56Asn in the COL6A2 gene has been reported previously in an individual affected with collagen VI-related dystrophy Inoue et al., 2021. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar as Uncertain significance. However, study on multiple affected individuals and the functional impact of the variant is not available. The amino acid Serine at position 56 is changed to an Asparagine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Ser56Asn in COL6A2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	28
Dann	Uncertain	0.98
DEOGEN2	Benign	0.36	T;.;D;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;.;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.2	M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N;D;N;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.62
MutPred		0.80		Loss of disorder (P = 0.0972);Loss of disorder (P = 0.0972);Loss of disorder (P = 0.0972);Loss of disorder (P = 0.0972);Loss of disorder (P = 0.0972);
MVP		0.98
MPC		0.58
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.58
gMVP		0.70

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: rs1555871311; hg19: chr21-47531944;