rs2850173

Positions:

• chr21-45992837-A-C
• chr21-45992837-A-G
• chr21-45992837-A-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.1335+27A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 1,571,902 control chromosomes in the GnomAD database, including 583,855 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (58848 hom., cov: 34)
  • Exomes 𝑓: 0.86 (525007 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.34

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=-0.91).
• BP6: Variant 21-45992837-A-C is Benign according to our data. Variant chr21-45992837-A-C is described in ClinVar as [Benign]. Clinvar id is 93811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45992837-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.1335+27A>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.1335+27A>C		intron_variant		1	NM_001848.3	ENSP00000355180	P1

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133594 AN: 152100 Hom.: 58785 Cov.: 34

Gnomad AFR AF: 0.922

Gnomad AMI AF: 0.826

Gnomad AMR AF: 0.904

Gnomad ASJ AF: 0.791

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.886

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.858

Gnomad OTH AF: 0.849

GnomAD3 exomes AF: 0.861 AC: 161350 AN: 187312 Hom.: 69638 AF XY: 0.854 AC XY: 85509 AN XY: 100128

Gnomad AFR exome AF: 0.921

Gnomad AMR exome AF: 0.925

Gnomad ASJ exome AF: 0.814

Gnomad EAS exome AF: 0.857

Gnomad SAS exome AF: 0.785

Gnomad FIN exome AF: 0.886

Gnomad NFE exome AF: 0.855

Gnomad OTH exome AF: 0.861

GnomAD4 exome AF: 0.859 AC: 1220047 AN: 1419684 Hom.: 525007 Cov.: 34 AF XY: 0.856 AC XY: 601530 AN XY: 702378

Gnomad4 AFR exome AF: 0.926

Gnomad4 AMR exome AF: 0.921

Gnomad4 ASJ exome AF: 0.803

Gnomad4 EAS exome AF: 0.877

Gnomad4 SAS exome AF: 0.786

Gnomad4 FIN exome AF: 0.889

Gnomad4 NFE exome AF: 0.861

Gnomad4 OTH exome AF: 0.852

GnomAD4 genome AF: 0.878 AC: 133714 AN: 152218 Hom.: 58848 Cov.: 34 AF XY: 0.878 AC XY: 65318 AN XY: 74424

Gnomad4 AFR AF: 0.922

Gnomad4 AMR AF: 0.905

Gnomad4 ASJ AF: 0.791

Gnomad4 EAS AF: 0.871

Gnomad4 SAS AF: 0.785

Gnomad4 FIN AF: 0.886

Gnomad4 NFE AF: 0.858

Gnomad4 OTH AF: 0.848

Alfa AF: 0.864 Hom.: 10423

Bravo AF: 0.883

Asia WGS AF: 0.825 AC: 2872 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

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	-0.91
CADD	Benign	1.1
DANN	Benign	0.52

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: rs2850173; hg19: chr21-47412751;