21-46124614-G-T

Position:

• chr21-46124614-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001849.4(COL6A2):​c.1672-37G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0815 in 1,606,578 control chromosomes in the GnomAD database, including 6,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (326 hom., cov: 33)
  • Exomes 𝑓: 0.084 (5706 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.364

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 21-46124614-G-T is Benign according to our data. Variant chr21-46124614-G-T is described in ClinVar as [Benign]. Clinvar id is 93917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124614-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.1672-37G>T		intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.1672-37G>T		intron_variant		ENST00000397763.6
COL6A2	NM_058175.3	c.1672-37G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.1672-37G>T		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.1672-37G>T		intron_variant		5	NM_058174.3
COL6A2	ENST00000409416.6	c.1672-37G>T		intron_variant		5
COL6A2	ENST00000413758.1	c.295-37G>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0578 AC: 8783 AN: 151964 Hom.: 327 Cov.: 33

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0448

Gnomad ASJ AF: 0.0784

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.0624

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.0904

Gnomad OTH AF: 0.0674

GnomAD3 exomes AF: 0.0634 AC: 15765 AN: 248770 Hom.: 625 AF XY: 0.0663 AC XY: 8967 AN XY: 135218

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.0369

Gnomad ASJ exome AF: 0.0783

Gnomad EAS exome AF: 0.0234

Gnomad SAS exome AF: 0.0634

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.0896

Gnomad OTH exome AF: 0.0684

GnomAD4 exome AF: 0.0840 AC: 122160 AN: 1454492 Hom.: 5706 Cov.: 29 AF XY: 0.0835 AC XY: 60474 AN XY: 724016

Gnomad4 AFR exome AF: 0.0159

Gnomad4 AMR exome AF: 0.0388

Gnomad4 ASJ exome AF: 0.0804

Gnomad4 EAS exome AF: 0.0214

Gnomad4 SAS exome AF: 0.0627

Gnomad4 FIN exome AF: 0.0290

Gnomad4 NFE exome AF: 0.0946

Gnomad4 OTH exome AF: 0.0785

GnomAD4 genome AF: 0.0577 AC: 8779 AN: 152086 Hom.: 326 Cov.: 33 AF XY: 0.0544 AC XY: 4041 AN XY: 74338

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.0447

Gnomad4 ASJ AF: 0.0784

Gnomad4 EAS AF: 0.0195

Gnomad4 SAS AF: 0.0623

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.0904

Gnomad4 OTH AF: 0.0662

Alfa AF: 0.0462 Hom.: 55

Bravo AF: 0.0579

Asia WGS AF: 0.0470 AC: 164 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2012	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.24
DANN	Benign	0.70

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: rs79205686; hg19: chr21-47544528;