21-45981967-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001848.3(COL6A1):c.97+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,567,822 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (22 hom., cov: 29)
  • Exomes 𝑓: 0.0017 (45 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.241

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=-0.81).
• BP6: Variant 21-45981967-G-A is Benign according to our data. Variant chr21-45981967-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0113 (1708/151778) while in subpopulation AFR AF= 0.0377 (1561/41410). AF 95% confidence interval is 0.0361. There are 22 homozygotes in gnomad4. There are 831 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.97+20G>A		intron_variant		ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.97+20G>A		intron_variant		1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1699 AN: 151658 Hom.: 21 Cov.: 29

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.00912

GnomAD3 exomes AF: 0.00326 AC: 682 AN: 209066 Hom.: 6 AF XY: 0.00258 AC XY: 295 AN XY: 114170

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00770

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000741

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000436

Gnomad OTH exome AF: 0.00321

GnomAD4 exome AF: 0.00168 AC: 2372 AN: 1416044 Hom.: 45 Cov.: 26 AF XY: 0.00156 AC XY: 1096 AN XY: 704716

Gnomad4 AFR exome AF: 0.0420

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.00795

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000145

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000356

Gnomad4 OTH exome AF: 0.00443

GnomAD4 genome AF: 0.0113 AC: 1708 AN: 151778 Hom.: 22 Cov.: 29 AF XY: 0.0112 AC XY: 831 AN XY: 74178

Gnomad4 AFR AF: 0.0377

Gnomad4 AMR AF: 0.00498

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000413

Gnomad4 OTH AF: 0.00902

Alfa AF: 0.00306 Hom.: 0

Bravo AF: 0.0134

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 20, 2021

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.5
Dann	Benign	0.57

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: rs114178849; hg19: chr21-47401881;