rs754507

Variant names:

• chr21-45986698-C-A
• rs754507
• NM_001848.3:c.588+13C>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45986698-C-A
• chr21-45986698-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001848.3(COL6A1):​c.588+13C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 1,543,586 control chromosomes in the GnomAD database, including 436,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38410 hom., cov: 31)
  • Exomes 𝑓: 0.75 (398163 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.155

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 21-45986698-C-A is Benign according to our data. Variant chr21-45986698-C-A is described in ClinVar as [Benign]. Clinvar id is 93879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45986698-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.588+13C>A		intron_variant	Intron 4 of 34	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.588+13C>A		intron_variant	Intron 4 of 34	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106351 AN: 151606 Hom.: 38390 Cov.: 31

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.848

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.762

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.842

Gnomad MID AF: 0.780

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.743

GnomAD3 exomes AF: 0.752 AC: 113636 AN: 151150 Hom.: 43093 AF XY: 0.752 AC XY: 60276 AN XY: 80110

Gnomad AFR exome AF: 0.518

Gnomad AMR exome AF: 0.768

Gnomad ASJ exome AF: 0.753

Gnomad EAS exome AF: 0.787

Gnomad SAS exome AF: 0.718

Gnomad FIN exome AF: 0.840

Gnomad NFE exome AF: 0.766

Gnomad OTH exome AF: 0.772

GnomAD4 exome AF: 0.755 AC: 1050445 AN: 1391858 Hom.: 398163 Cov.: 57 AF XY: 0.755 AC XY: 518132 AN XY: 686646

Gnomad4 AFR exome AF: 0.499

Gnomad4 AMR exome AF: 0.770

Gnomad4 ASJ exome AF: 0.755

Gnomad4 EAS exome AF: 0.754

Gnomad4 SAS exome AF: 0.719

Gnomad4 FIN exome AF: 0.836

Gnomad4 NFE exome AF: 0.761

Gnomad4 OTH exome AF: 0.754

GnomAD4 genome AF: 0.701 AC: 106415 AN: 151728 Hom.: 38410 Cov.: 31 AF XY: 0.705 AC XY: 52240 AN XY: 74148

Gnomad4 AFR AF: 0.515

Gnomad4 AMR AF: 0.755

Gnomad4 ASJ AF: 0.762

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.722

Gnomad4 FIN AF: 0.842

Gnomad4 NFE AF: 0.767

Gnomad4 OTH AF: 0.746

Alfa AF: 0.734 Hom.: 8385

Bravo AF: 0.689

Asia WGS AF: 0.775 AC: 2694 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Apr 15, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2014

Eurofins Ntd Llc (ga)

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

- -

Jan 25, 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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Collagen 6-related myopathy Benign:1

Jan 13, 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. -

Ullrich congenital muscular dystrophy 1A Benign:1

Jul 30, 2021

Genome-Nilou Lab

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	-0.78
CADD	Benign	3.4
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs754507; hg19: chr21-47406612; COSMIC: COSV62616090; COSMIC: COSV62616090;