rs138646508

chr21-45984365-C-Tchr21-45984365-C-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001848.3(COL6A1):c.324C>T(p.Gly108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,612,568 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 35)
  • Exomes 𝑓: 0.0018 (10 hom.)
• Consequence: COL6A1 NM_001848.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.21

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 21-45984365-C-T is Benign according to our data. Variant chr21-45984365-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 196329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.324C>T	p.Gly108=	synonymous_variant	3/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.324C>T	p.Gly108=	synonymous_variant	3/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 152254 Hom.: 3 Cov.: 35

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00181 AC: 450 AN: 249038 Hom.: 2 AF XY: 0.00164 AC XY: 222 AN XY: 135328

Gnomad AFR exome AF: 0.000376

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00211

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00753

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.00178 AC: 2606 AN: 1460196 Hom.: 10 Cov.: 32 AF XY: 0.00173 AC XY: 1257 AN XY: 726392

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00603

Gnomad4 NFE exome AF: 0.00187

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00184 AC: 281 AN: 152372 Hom.: 3 Cov.: 35 AF XY: 0.00207 AC XY: 154 AN XY: 74508

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00678

Gnomad4 NFE AF: 0.00273

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00240 Hom.: 2

Bravo AF: 0.00107

EpiCase AF: 0.00169

EpiControl AF: 0.00119

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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	COL6A1: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 27, 2016

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	4.7
Dann	Benign	0.86

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: rs138646508; hg19: chr21-47404279;