chr21-45990401-C-T

Position:

• chr21-45990401-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001848.3(COL6A1):​c.981C>T​(p.Ile327=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,371,302 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: COL6A1 NM_001848.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.29

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 21-45990401-C-T is Benign according to our data. Variant chr21-45990401-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.29 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.981C>T	p.Ile327=	synonymous_variant	13/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.981C>T	p.Ile327=	synonymous_variant	13/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.000666 AC: 73 AN: 109616 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000377

Gnomad FIN AF: 0.000643

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000863

Gnomad OTH AF: 0.000683

GnomAD3 exomes AF: 0.000730 AC: 162 AN: 221830 Hom.: 0 AF XY: 0.000709 AC XY: 86 AN XY: 121252

Gnomad AFR exome AF: 0.000576

Gnomad AMR exome AF: 0.000878

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000287

Gnomad SAS exome AF: 0.0000734

Gnomad FIN exome AF: 0.000476

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00124 AC: 1559 AN: 1261566 Hom.: 1 Cov.: 49 AF XY: 0.00120 AC XY: 748 AN XY: 625088

Gnomad4 AFR exome AF: 0.000351

Gnomad4 AMR exome AF: 0.000938

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000932

Gnomad4 SAS exome AF: 0.0000250

Gnomad4 FIN exome AF: 0.000653

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.000674 AC: 74 AN: 109736 Hom.: 0 Cov.: 24 AF XY: 0.000478 AC XY: 25 AN XY: 52354

Gnomad4 AFR AF: 0.000310

Gnomad4 AMR AF: 0.00134

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000377

Gnomad4 FIN AF: 0.000643

Gnomad4 NFE AF: 0.000863

Gnomad4 OTH AF: 0.00135

Alfa AF: 0.000886 Hom.: 0

Bravo AF: 0.000616

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	COL6A1: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Benign	0.88

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: rs138401567; hg19: chr21-47410315;