rs2236486

Variant names:

• chr21-46002730-G-A
• rs2236486
• NM_001848.3:c.2434+20G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46002730-G-A
• chr21-46002730-G-C

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.2434+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,532,036 control chromosomes in the GnomAD database, including 96,516 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8640 hom., cov: 36)
  • Exomes 𝑓: 0.34 (87876 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.735
• Publications: 10 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=-0.86).
• BP6: Variant 21-46002730-G-A is Benign according to our data. Variant chr21-46002730-G-A is described in ClinVar as Benign. ClinVar VariationId is 93855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.2434+20G>A		intron_variant	Intron 33 of 34	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.2434+20G>A		intron_variant	Intron 33 of 34	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48698 AN: 151066 Hom.: 8630 Cov.: 36

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.342

GnomAD2 exomes AF: 0.383 AC: 87646 AN: 229102 AF XY: 0.378

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.523

Gnomad ASJ exome AF: 0.385

Gnomad EAS exome AF: 0.642

Gnomad FIN exome AF: 0.376

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.383

GnomAD4 exome AF: 0.343 AC: 473683 AN: 1380850 Hom.: 87876 Cov.: 42 AF XY: 0.346 AC XY: 237633 AN XY: 687702

African (AFR) AF: 0.193 AC: 5964 AN: 30850

American (AMR) AF: 0.526 AC: 22119 AN: 42076

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 9799 AN: 25376

East Asian (EAS) AF: 0.626 AC: 24333 AN: 38868

South Asian (SAS) AF: 0.396 AC: 32186 AN: 81326

European-Finnish (FIN) AF: 0.396 AC: 19435 AN: 49132

Middle Eastern (MID) AF: 0.381 AC: 2057 AN: 5404

European-Non Finnish (NFE) AF: 0.321 AC: 337286 AN: 1050562

Other (OTH) AF: 0.358 AC: 20504 AN: 57256

GnomAD4 genome AF: 0.322 AC: 48721 AN: 151186 Hom.: 8640 Cov.: 36 AF XY: 0.327 AC XY: 24175 AN XY: 73866

African (AFR) AF: 0.201 AC: 8270 AN: 41084

American (AMR) AF: 0.423 AC: 6441 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1337 AN: 3464

East Asian (EAS) AF: 0.633 AC: 3229 AN: 5100

South Asian (SAS) AF: 0.398 AC: 1902 AN: 4780

European-Finnish (FIN) AF: 0.385 AC: 4052 AN: 10518

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22277 AN: 67706

Other (OTH) AF: 0.346 AC: 727 AN: 2100

Alfa AF: 0.330 Hom.: 1377

Bravo AF: 0.322

Asia WGS AF: 0.485 AC: 1659 AN: 3424

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -

Dec 09, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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	-0.86
CADD	Benign	13
DANN	Benign	0.64
PhyloP100		0.73
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs2236486; hg19: chr21-47422644; COSMIC: COSV62615168; COSMIC: COSV62615168;