21-46126468-C-A

Position:

• chr21-46126468-C-A

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.2423-35C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.089 in 1,608,332 control chromosomes in the GnomAD database, including 7,234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (493 hom., cov: 33)
  • Exomes 𝑓: 0.090 (6741 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.468

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=-0.85).
• BP6: Variant 21-46126468-C-A is Benign according to our data. Variant chr21-46126468-C-A is described in ClinVar as [Benign]. Clinvar id is 93939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46126468-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.2423-35C>A		intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.2423-35C>A		intron_variant		ENST00000397763.6
COL6A2	NM_058175.3	c.2423-35C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.2423-35C>A		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.2423-35C>A		intron_variant		5	NM_058174.3
COL6A2	ENST00000409416.6	c.2423-35C>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0777 AC: 11817 AN: 152060 Hom.: 491 Cov.: 33

Gnomad AFR AF: 0.0768

Gnomad AMI AF: 0.0672

Gnomad AMR AF: 0.0500

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0909

Gnomad OTH AF: 0.0809

GnomAD3 exomes AF: 0.0736 AC: 18264 AN: 248244 Hom.: 944 AF XY: 0.0791 AC XY: 10621 AN XY: 134324

Gnomad AFR exome AF: 0.0759

Gnomad AMR exome AF: 0.0374

Gnomad ASJ exome AF: 0.0752

Gnomad EAS exome AF: 0.0239

Gnomad SAS exome AF: 0.147

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0816

Gnomad OTH exome AF: 0.0743

GnomAD4 exome AF: 0.0901 AC: 131232 AN: 1456154 Hom.: 6741 Cov.: 33 AF XY: 0.0917 AC XY: 66468 AN XY: 724626

Gnomad4 AFR exome AF: 0.0808

Gnomad4 AMR exome AF: 0.0415

Gnomad4 ASJ exome AF: 0.0801

Gnomad4 EAS exome AF: 0.0229

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.0285

Gnomad4 NFE exome AF: 0.0938

Gnomad4 OTH exome AF: 0.0889

GnomAD4 genome AF: 0.0777 AC: 11830 AN: 152178 Hom.: 493 Cov.: 33 AF XY: 0.0749 AC XY: 5573 AN XY: 74398

Gnomad4 AFR AF: 0.0768

Gnomad4 AMR AF: 0.0500

Gnomad4 ASJ AF: 0.0778

Gnomad4 EAS AF: 0.0242

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.0909

Gnomad4 OTH AF: 0.0853

Alfa AF: 0.0434 Hom.: 48

Bravo AF: 0.0780

Asia WGS AF: 0.121 AC: 422 AN: 3476

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	-0.85
CADD	Benign	1.8
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs16978878; hg19: chr21-47546382;