rs114178849

Variant names:

• chr21-45981967-G-A
• rs114178849
• NM_001848.3:c.97+20G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45981967-G-A
• chr21-45981967-G-C
• chr21-45981967-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001848.3(COL6A1):​c.97+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,567,822 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (22 hom., cov: 29)
  • Exomes 𝑓: 0.0017 (45 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.241
• Publications: 0 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=-0.81).
• BP6: Variant 21-45981967-G-A is Benign according to our data. Variant chr21-45981967-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1708/151778) while in subpopulation AFR AF = 0.0377 (1561/41410). AF 95% confidence interval is 0.0361. There are 22 homozygotes in GnomAd4. There are 831 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001848.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.97+20G>A		intron	N/A	NP_001839.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.97+20G>A		intron	N/A	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1699 AN: 151658 Hom.: 21 Cov.: 29

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.00912

GnomAD2 exomes AF: 0.00326 AC: 682 AN: 209066 AF XY: 0.00258

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00770

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000436

Gnomad OTH exome AF: 0.00321

GnomAD4 exome AF: 0.00168 AC: 2372 AN: 1416044 Hom.: 45 Cov.: 26 AF XY: 0.00156 AC XY: 1096 AN XY: 704716

African (AFR) AF: 0.0420 AC: 1363 AN: 32490

American (AMR) AF: 0.00304 AC: 130 AN: 42788

Ashkenazi Jewish (ASJ) AF: 0.00795 AC: 203 AN: 25528

East Asian (EAS) AF: 0.00 AC: 0 AN: 38622

South Asian (SAS) AF: 0.000145 AC: 12 AN: 82794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50560

Middle Eastern (MID) AF: 0.00409 AC: 20 AN: 4886

European-Non Finnish (NFE) AF: 0.000356 AC: 384 AN: 1079742

Other (OTH) AF: 0.00443 AC: 260 AN: 58634

GnomAD4 genome AF: 0.0113 AC: 1708 AN: 151778 Hom.: 22 Cov.: 29 AF XY: 0.0112 AC XY: 831 AN XY: 74178

African (AFR) AF: 0.0377 AC: 1561 AN: 41410

American (AMR) AF: 0.00498 AC: 76 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5032

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000413 AC: 28 AN: 67876

Other (OTH) AF: 0.00902 AC: 19 AN: 2106

Alfa AF: 0.00413 Hom.: 1

Bravo AF: 0.0134

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 15, 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

Jul 15, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Benign:1

Sep 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bethlem myopathy 1A Benign:1

Jan 28, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.5
DANN	Benign	0.57
PhyloP100		0.24
PromoterAI		-0.0020	Neutral
Mutation Taster		=100/0	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: rs114178849; hg19: chr21-47401881;