chr21-45981846-C-G

Position:

• chr21-45981846-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.-5C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,574,586 control chromosomes in the GnomAD database, including 216,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18376 hom., cov: 24)
  • Exomes 𝑓: 0.52 (198437 hom.)
• Consequence: COL6A1 NM_001848.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.257

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=-0.9).
• BP6: Variant 21-45981846-C-G is Benign according to our data. Variant chr21-45981846-C-G is described in ClinVar as [Benign]. Clinvar id is 93792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45981846-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.-5C>G		5_prime_UTR_variant	1/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.-5C>G		5_prime_UTR_variant	1/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.477 AC: 71156 AN: 149192 Hom.: 18365 Cov.: 24

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.660

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.539

GnomAD3 exomes AF: 0.555 AC: 104340 AN: 188092 Hom.: 29837 AF XY: 0.557 AC XY: 57300 AN XY: 102834

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.604

Gnomad ASJ exome AF: 0.573

Gnomad EAS exome AF: 0.774

Gnomad SAS exome AF: 0.604

Gnomad FIN exome AF: 0.557

Gnomad NFE exome AF: 0.516

Gnomad OTH exome AF: 0.576

GnomAD4 exome AF: 0.523 AC: 744998 AN: 1425282 Hom.: 198437 Cov.: 34 AF XY: 0.527 AC XY: 372074 AN XY: 706378

Gnomad4 AFR exome AF: 0.272

Gnomad4 AMR exome AF: 0.604

Gnomad4 ASJ exome AF: 0.580

Gnomad4 EAS exome AF: 0.748

Gnomad4 SAS exome AF: 0.606

Gnomad4 FIN exome AF: 0.563

Gnomad4 NFE exome AF: 0.509

Gnomad4 OTH exome AF: 0.539

GnomAD4 genome AF: 0.477 AC: 71194 AN: 149304 Hom.: 18376 Cov.: 24 AF XY: 0.482 AC XY: 35079 AN XY: 72772

Gnomad4 AFR AF: 0.284

Gnomad4 AMR AF: 0.555

Gnomad4 ASJ AF: 0.583

Gnomad4 EAS AF: 0.770

Gnomad4 SAS AF: 0.619

Gnomad4 FIN AF: 0.562

Gnomad4 NFE AF: 0.521

Gnomad4 OTH AF: 0.544

Alfa AF: 0.490 Hom.: 5441

Bravo AF: 0.470

Asia WGS AF: 0.703 AC: 2443 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2016	- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.7
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs7671; hg19: chr21-47401760;