21-46125455-A-AC

Position:

• chr21-46125455-A-AC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001849.4(COL6A2):​c.1817-3dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,609,932 control chromosomes in the GnomAD database, including 16,150 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1289 hom., cov: 30)
  • Exomes 𝑓: 0.13 (14861 hom.)
• Consequence: COL6A2 NM_001849.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.481

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 -16 ACMG points.

• BP6: Variant 21-46125455-A-AC is Benign according to our data. Variant chr21-46125455-A-AC is described in ClinVar as [Benign]. Clinvar id is 93925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1817-3dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1817-3dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1817-3dup		splice_polypyrimidine_tract_variant, intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1817-3dup		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1817-3dup		splice_polypyrimidine_tract_variant, intron_variant		5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000413758.1	c.485dup	p.Asp163ArgfsTer3	frameshift_variant	10/11	3		ENSP00000395751
COL6A2	ENST00000409416.6	c.1817-3dup		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000387115

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18039 AN: 151672 Hom.: 1289 Cov.: 30

Gnomad AFR AF: 0.0921

Gnomad AMI AF: 0.0782

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0589

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.140

GnomAD3 exomes AF: 0.130 AC: 32417 AN: 249506 Hom.: 2634 AF XY: 0.128 AC XY: 17355 AN XY: 135402

Gnomad AFR exome AF: 0.0940

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.338

Gnomad SAS exome AF: 0.0959

Gnomad FIN exome AF: 0.0609

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.133 AC: 193389 AN: 1458142 Hom.: 14861 Cov.: 52 AF XY: 0.131 AC XY: 95357 AN XY: 725414

Gnomad4 AFR exome AF: 0.0905

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.408

Gnomad4 SAS exome AF: 0.0930

Gnomad4 FIN exome AF: 0.0639

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.119 AC: 18046 AN: 151790 Hom.: 1289 Cov.: 30 AF XY: 0.118 AC XY: 8765 AN XY: 74192

Gnomad4 AFR AF: 0.0920

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.348

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0589

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.141

Bravo AF: 0.124

EpiCase AF: 0.133

EpiControl AF: 0.132

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: High allele frequency. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2012	- -

Bethlem myopathy 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Myosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 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

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: rs149954350; hg19: chr21-47545369;