rs2070957

Positions:

• chr21-46112622-C-T
• chr21-46112622-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.714+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 1,601,862 control chromosomes in the GnomAD database, including 6,158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (1193 hom., cov: 32)
  • Exomes 𝑓: 0.052 (4965 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.278

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]

COL6A2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-46112622-C-T is Benign according to our data. Variant chr21-46112622-C-T is described in ClinVar as [Benign]. Clinvar id is 93958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46112622-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.714+45C>T		intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.714+45C>T		intron_variant			NP_478054.2
COL6A2	NM_058175.3	c.714+45C>T		intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.714+45C>T		intron_variant		1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.714+45C>T		intron_variant		5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.714+45C>T		intron_variant		5		ENSP00000387115.1
COL6A2	ENST00000460886.1	n.160+45C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0967 AC: 14698 AN: 152034 Hom.: 1191 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.0716

Gnomad AMR AF: 0.0963

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.0876

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0358

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.0804 AC: 19368 AN: 240852 Hom.: 1502 AF XY: 0.0754 AC XY: 9939 AN XY: 131752

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0327

Gnomad EAS exome AF: 0.289

Gnomad SAS exome AF: 0.0817

Gnomad FIN exome AF: 0.0187

Gnomad NFE exome AF: 0.0379

Gnomad OTH exome AF: 0.0599

GnomAD4 exome AF: 0.0524 AC: 76026 AN: 1449708 Hom.: 4965 Cov.: 33 AF XY: 0.0527 AC XY: 38028 AN XY: 721420

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.0337

Gnomad4 EAS exome AF: 0.366

Gnomad4 SAS exome AF: 0.0783

Gnomad4 FIN exome AF: 0.0191

Gnomad4 NFE exome AF: 0.0338

Gnomad4 OTH exome AF: 0.0654

GnomAD4 genome AF: 0.0967 AC: 14720 AN: 152154 Hom.: 1193 Cov.: 32 AF XY: 0.0972 AC XY: 7234 AN XY: 74416

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.0960

Gnomad4 ASJ AF: 0.0369

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.0879

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0358

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0238 Hom.: 15

Bravo AF: 0.109

Asia WGS AF: 0.163 AC: 567 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2012	- -

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	-0.89
CADD	Benign	2.8
DANN	Benign	0.81

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: rs2070957; hg19: chr21-47532536; COSMIC: COSV56001721; COSMIC: COSV56001721;