rs377195134

Variant names:

• chr21-46132557-G-A
• rs377195134
• NM_001849.4:c.*5G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001849.4(COL6A2):​c.*5G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 1,588,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: COL6A2 NM_001849.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -1.18
• Publications: 0 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.*5G>A		3_prime_UTR_variant	Exon 28 of 28	ENST00000300527.9	NP_001840.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.*5G>A		3_prime_UTR_variant	Exon 28 of 28	1	NM_001849.4	ENSP00000300527.4

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152230 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000795 AC: 16 AN: 201226 AF XY: 0.0000630

Gnomad AFR exome AF: 0.000818

Gnomad AMR exome AF: 0.0000317

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000190

Gnomad FIN exome AF: 0.0000837

Gnomad NFE exome AF: 0.0000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000286 AC: 41 AN: 1436070 Hom.: 0 Cov.: 34 AF XY: 0.0000266 AC XY: 19 AN XY: 713746

African (AFR) AF: 0.000513 AC: 17 AN: 33128

American (AMR) AF: 0.0000234 AC: 1 AN: 42776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.0000772 AC: 3 AN: 38854

South Asian (SAS) AF: 0.0000356 AC: 3 AN: 84256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41372

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.0000109 AC: 12 AN: 1104510

Other (OTH) AF: 0.0000671 AC: 4 AN: 59630

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152348 Hom.: 0 Cov.: 34 AF XY: 0.000188 AC XY: 14 AN XY: 74496

African (AFR) AF: 0.000649 AC: 27 AN: 41582

American (AMR) AF: 0.000261 AC: 4 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000242

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1 Benign:1

-

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 11, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

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: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.23
DANN	Benign	0.91
PhyloP100		-1.2

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: rs377195134; hg19: chr21-47552471; COSMIC: COSV52430698; COSMIC: COSV52430698;