rs9976026

Positions:

• chr21-46122072-T-C

Variant summary

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

The ENST00000300527.9(COL6A2):​c.1522-36T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,609,124 control chromosomes in the GnomAD database, including 24,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1411 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22834 hom.)
• Consequence: COL6A2 ENST00000300527.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.847

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=-0.86).
• BP6: Variant 21-46122072-T-C is Benign according to our data. Variant chr21-46122072-T-C is described in ClinVar as [Benign]. Clinvar id is 93910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46122072-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1522-36T>C		intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1522-36T>C		intron_variant		ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1522-36T>C		intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1522-36T>C		intron_variant		1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1522-36T>C		intron_variant		5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.1522-36T>C		intron_variant		5		ENSP00000387115
COL6A2	ENST00000413758.1	c.145-36T>C		intron_variant		3		ENSP00000395751

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18539 AN: 151970 Hom.: 1413 Cov.: 32

Gnomad AFR AF: 0.0657

Gnomad AMI AF: 0.0749

Gnomad AMR AF: 0.0949

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.0746

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.120 AC: 29642 AN: 246176 Hom.: 2197 AF XY: 0.124 AC XY: 16580 AN XY: 133832

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.0700

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.0244

Gnomad SAS exome AF: 0.0788

Gnomad FIN exome AF: 0.0616

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.168 AC: 244626 AN: 1457036 Hom.: 22834 Cov.: 32 AF XY: 0.165 AC XY: 119820 AN XY: 724920

Gnomad4 AFR exome AF: 0.0588

Gnomad4 AMR exome AF: 0.0741

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.0225

Gnomad4 SAS exome AF: 0.0783

Gnomad4 FIN exome AF: 0.0677

Gnomad4 NFE exome AF: 0.193

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.122 AC: 18546 AN: 152088 Hom.: 1411 Cov.: 32 AF XY: 0.115 AC XY: 8546 AN XY: 74348

Gnomad4 AFR AF: 0.0659

Gnomad4 AMR AF: 0.0948

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.0196

Gnomad4 SAS AF: 0.0741

Gnomad4 FIN AF: 0.0613

Gnomad4 NFE AF: 0.183

Gnomad4 OTH AF: 0.131

Alfa AF: 0.152 Hom.: 490

Bravo AF: 0.123

Asia WGS AF: 0.0660 AC: 229 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

not provided Benign:2

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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.48
DANN	Benign	0.68

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: rs9976026; hg19: chr21-47541986;