21-45997389-T-C

Position:

• chr21-45997389-T-C

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.1399-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,605,044 control chromosomes in the GnomAD database, including 222,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19486 hom., cov: 32)
  • Exomes 𝑓: 0.52 (203016 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.03

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-45997389-T-C is Benign according to our data. Variant chr21-45997389-T-C is described in ClinVar as [Benign]. Clinvar id is 93813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45997389-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.1399-32T>C		intron_variant		ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.1399-32T>C		intron_variant		1	NM_001848.3	ENSP00000355180.3
COL6A1	ENST00000683550.1	n.174-32T>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75679 AN: 151746 Hom.: 19465 Cov.: 32

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.509

GnomAD3 exomes AF: 0.548 AC: 137059 AN: 250246 Hom.: 39151 AF XY: 0.537 AC XY: 72848 AN XY: 135604

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.754

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.674

Gnomad SAS exome AF: 0.463

Gnomad FIN exome AF: 0.511

Gnomad NFE exome AF: 0.522

Gnomad OTH exome AF: 0.538

GnomAD4 exome AF: 0.524 AC: 761770 AN: 1453180 Hom.: 203016 Cov.: 32 AF XY: 0.522 AC XY: 377565 AN XY: 723416

Gnomad4 AFR exome AF: 0.371

Gnomad4 AMR exome AF: 0.740

Gnomad4 ASJ exome AF: 0.496

Gnomad4 EAS exome AF: 0.651

Gnomad4 SAS exome AF: 0.469

Gnomad4 FIN exome AF: 0.523

Gnomad4 NFE exome AF: 0.522

Gnomad4 OTH exome AF: 0.509

GnomAD4 genome AF: 0.499 AC: 75746 AN: 151864 Hom.: 19486 Cov.: 32 AF XY: 0.501 AC XY: 37143 AN XY: 74200

Gnomad4 AFR AF: 0.384

Gnomad4 AMR AF: 0.641

Gnomad4 ASJ AF: 0.494

Gnomad4 EAS AF: 0.668

Gnomad4 SAS AF: 0.469

Gnomad4 FIN AF: 0.516

Gnomad4 NFE AF: 0.523

Gnomad4 OTH AF: 0.513

Alfa AF: 0.516 Hom.: 29692

Bravo AF: 0.507

Asia WGS AF: 0.568 AC: 1974 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2012	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Ullrich congenital muscular dystrophy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.65
DANN	Benign	0.48

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: rs2839077; hg19: chr21-47417303; COSMIC: COSV62612066; COSMIC: COSV62612066;