rs201188174

chr21-46132385-C-Tchr21-46132385-C-Achr21-46132385-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BP6

The NM_001849.4(COL6A2):c.2893C>T(p.Arg965Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,609,486 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. R965H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 2.45

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 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77
• BP6: Variant 21-46132385-C-T is Benign according to our data. Variant chr21-46132385-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283255.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.2893C>T	p.Arg965Cys	missense_variant	28/28	ENST00000300527.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.2893C>T	p.Arg965Cys	missense_variant	28/28	1	NM_001849.4	P1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152236 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000175 AC: 43 AN: 245502 Hom.: 0 AF XY: 0.000164 AC XY: 22 AN XY: 133814

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.000314

Gnomad NFE exome AF: 0.000288

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000405 AC: 590 AN: 1457132 Hom.: 0 Cov.: 35 AF XY: 0.000383 AC XY: 278 AN XY: 724976

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000464

Gnomad4 NFE exome AF: 0.000459

Gnomad4 OTH exome AF: 0.000746

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152354 Hom.: 0 Cov.: 34 AF XY: 0.000282 AC XY: 21 AN XY: 74504

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000332 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30564623) -

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.2893C>T in COL6A2 has been submitted to ClinVar as a Variant of Uncertain Significance (VUS), but no details are available for independent assessment. This variant has been observed in an individual with clinical suspicion of limb-girdle muscular dystrophy (Nallamilli et. al., 2018). The p.Arg965Cys variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.02% in gnomAD database. The amino acid Arg at position 965 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg965Cys in COL6A2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS). -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.58
MVP		0.97
MPC		0.69
ClinPred		0.46	T
GERP RS		3.4
Varity_R		0.37
gMVP		0.86

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: rs201188174; hg19: chr21-47552299; COSMIC: COSV52424523; COSMIC: COSV52424523;