rs2276254

Variant names:

• chr21-45997501-C-A
• rs2276254
• NM_001848.3:c.1461+18C>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45997501-C-A
• chr21-45997501-C-G
• chr21-45997501-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001848.3(COL6A1):​c.1461+18C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 1,606,648 control chromosomes in the GnomAD database, including 265,516 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (24267 hom., cov: 32)
  • Exomes 𝑓: 0.57 (241249 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.72
• Publications: 13 publications found

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• Ullrich congenital muscular dystrophy 1A

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-45997501-C-A is Benign according to our data. Variant chr21-45997501-C-A is described in ClinVar as Benign. ClinVar VariationId is 93815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.1461+18C>A		intron_variant	Intron 21 of 34	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.1461+18C>A		intron_variant	Intron 21 of 34	1	NM_001848.3	ENSP00000355180.3
COL6A1	ENST00000683550.1	n.236+18C>A		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes AF: 0.576 AC: 85343 AN: 148084 Hom.: 24243 Cov.: 32

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.753

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.565

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.580

GnomAD2 exomes AF: 0.598 AC: 147745 AN: 247130 AF XY: 0.595

Gnomad AFR exome AF: 0.510

Gnomad AMR exome AF: 0.636

Gnomad ASJ exome AF: 0.589

Gnomad EAS exome AF: 0.744

Gnomad FIN exome AF: 0.638

Gnomad NFE exome AF: 0.573

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.573 AC: 835886 AN: 1458448 Hom.: 241249 Cov.: 39 AF XY: 0.573 AC XY: 416165 AN XY: 725684

African (AFR) AF: 0.495 AC: 16550 AN: 33434

American (AMR) AF: 0.632 AC: 28255 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 15181 AN: 26116

East Asian (EAS) AF: 0.733 AC: 29103 AN: 39684

South Asian (SAS) AF: 0.572 AC: 49334 AN: 86218

European-Finnish (FIN) AF: 0.636 AC: 33159 AN: 52126

Middle Eastern (MID) AF: 0.555 AC: 3177 AN: 5720

European-Non Finnish (NFE) AF: 0.564 AC: 625837 AN: 1110164

Other (OTH) AF: 0.585 AC: 35290 AN: 60300

GnomAD4 genome AF: 0.576 AC: 85418 AN: 148200 Hom.: 24267 Cov.: 32 AF XY: 0.578 AC XY: 41811 AN XY: 72286

African (AFR) AF: 0.514 AC: 20660 AN: 40228

American (AMR) AF: 0.612 AC: 9016 AN: 14740

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 2036 AN: 3410

East Asian (EAS) AF: 0.752 AC: 3831 AN: 5094

South Asian (SAS) AF: 0.591 AC: 2814 AN: 4760

European-Finnish (FIN) AF: 0.645 AC: 6643 AN: 10306

Middle Eastern (MID) AF: 0.559 AC: 161 AN: 288

European-Non Finnish (NFE) AF: 0.580 AC: 38501 AN: 66428

Other (OTH) AF: 0.580 AC: 1198 AN: 2064

Alfa AF: 0.505 Hom.: 2811

Bravo AF: 0.558

Asia WGS AF: 0.661 AC: 2295 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Bethlem myopathy 1A Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2276254; hg19: chr21-47417415; COSMIC: COSV107450280; COSMIC: COSV107450280;