rs75581470

Variant names:

• chr21-46121586-C-A
• rs75581470
• NM_001849.4:c.1489C>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46121586-C-A
• chr21-46121586-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001849.4(COL6A2):​c.1489C>A​(p.Pro497Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.64
• Publications: 5 publications found

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]

COL6A2 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014317423).
• BP6: Variant 21-46121586-C-A is Benign according to our data. Variant chr21-46121586-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284555.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1489C>A	p.Pro497Thr	missense_variant	Exon 18 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1489C>A	p.Pro497Thr	missense_variant	Exon 18 of 28		NP_478054.2
COL6A2	NM_058175.3	c.1489C>A	p.Pro497Thr	missense_variant	Exon 18 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1489C>A	p.Pro497Thr	missense_variant	Exon 18 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1489C>A	p.Pro497Thr	missense_variant	Exon 18 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1489C>A	p.Pro497Thr	missense_variant	Exon 17 of 27	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.112C>A	p.Pro38Thr	missense_variant	Exon 3 of 11	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152114 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00658

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000416 AC: 104 AN: 249838 AF XY: 0.000413

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00539

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1460530 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 89 AN XY: 726572

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00463 AC: 184 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111936

Other (OTH) AF: 0.0000994 AC: 6 AN: 60376

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152232 Hom.: 0 Cov.: 34 AF XY: 0.000255 AC XY: 19 AN XY: 74442

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00660 AC: 34 AN: 5154

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000442 Hom.: 0

Bravo AF: 0.000204

ExAC AF: 0.000355 AC: 43

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jul 18, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the COL6A2 gene. The P497T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P497T variant is observed in 41/8600 (0.5%) alleles from individuals of East Asian background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P497T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not specified Benign:1

Nov 24, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myosclerosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Collagen 6-related myopathy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COL6A2-related disorder Benign:1

Sep 30, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;.;.;D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T;.;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.014	T;T;T;T;T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.
PhyloP100		2.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Benign	0.053	T;D;D;D;D
Sift4G	Benign	0.097	T;T;T;T;D
Polyphen		0.87	P;P;P;P;.
Vest4		0.53
MVP		0.99
MPC		0.20
ClinPred		0.10	T
GERP RS		4.2
Varity_R		0.18
gMVP		0.34
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs75581470; hg19: chr21-47541500;