rs139243418

chr21-45998406-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001848.3(COL6A1):c.1584G>A(p.Pro528=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 1,613,150 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00073 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00057 (1 hom.)
• Consequence: COL6A1 NM_001848.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -2.00

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 21-45998406-G-A is Benign according to our data. Variant chr21-45998406-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258287.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.1584G>A	p.Pro528=	synonymous_variant	24/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.1584G>A	p.Pro528=	synonymous_variant	24/35	1	NM_001848.3	P1
COL6A1	ENST00000683550.1	n.359G>A		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.000730 AC: 111 AN: 152108 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000654 AC: 164 AN: 250600 Hom.: 0 AF XY: 0.000626 AC XY: 85 AN XY: 135734

Gnomad AFR exome AF: 0.000743

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.000663

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000570 AC: 832 AN: 1460922 Hom.: 1 Cov.: 33 AF XY: 0.000534 AC XY: 388 AN XY: 726776

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00316

Gnomad4 NFE exome AF: 0.000550

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152228 Hom.: 1 Cov.: 34 AF XY: 0.000820 AC XY: 61 AN XY: 74422

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000656 Hom.: 0

Bravo AF: 0.000495

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 13, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	COL6A1: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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. -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	1.9
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139243418; hg19: chr21-47418320; COSMIC: COSV100720151; COSMIC: COSV100720151;