rs2276254

Positions:

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

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.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:6
• Conservation: PhyloP100: -1.72

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=-0.83).
• BP6: Variant 21-45997501-C-A is Benign according to our data. Variant chr21-45997501-C-A is described in ClinVar as [Benign]. Clinvar id is 93815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45997501-C-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
COL6A1	NM_001848.3	c.1461+18C>A		intron_variant		ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.1461+18C>A		intron_variant		1	NM_001848.3	P1
COL6A1	ENST00000683550.1	n.236+18C>A		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.598 AC: 147745 AN: 247130 Hom.: 44449 AF XY: 0.595 AC XY: 79958 AN XY: 134408

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 SAS exome AF: 0.575

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

Gnomad4 AFR exome AF: 0.495

Gnomad4 AMR exome AF: 0.632

Gnomad4 ASJ exome AF: 0.581

Gnomad4 EAS exome AF: 0.733

Gnomad4 SAS exome AF: 0.572

Gnomad4 FIN exome AF: 0.636

Gnomad4 NFE exome AF: 0.564

Gnomad4 OTH exome AF: 0.585

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

Gnomad4 AFR AF: 0.514

Gnomad4 AMR AF: 0.612

Gnomad4 ASJ AF: 0.597

Gnomad4 EAS AF: 0.752

Gnomad4 SAS AF: 0.591

Gnomad4 FIN AF: 0.645

Gnomad4 NFE AF: 0.580

Gnomad4 OTH AF: 0.580

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.63

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: rs2276254; hg19: chr21-47417415;