chr21-46125241-A-G

Position:

• chr21-46125241-A-G

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.1771-25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 1,608,110 control chromosomes in the GnomAD database, including 528,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.81 (49786 hom., cov: 33)
  • Exomes 𝑓: 0.81 (478986 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.607

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: This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-46125241-A-G is Benign according to our data. Variant chr21-46125241-A-G is described in ClinVar as [Benign]. Clinvar id is 93922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46125241-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1771-25A>G		intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1771-25A>G		intron_variant			NP_478054.2
COL6A2	NM_058175.3	c.1771-25A>G		intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1771-25A>G		intron_variant		1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1771-25A>G		intron_variant		5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1771-25A>G		intron_variant		5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.394-25A>G		intron_variant		3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122787 AN: 152032 Hom.: 49733 Cov.: 33

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.835

GnomAD3 exomes AF: 0.803 AC: 199929 AN: 248836 Hom.: 81173 AF XY: 0.792 AC XY: 106701 AN XY: 134800

Gnomad AFR exome AF: 0.786

Gnomad AMR exome AF: 0.903

Gnomad ASJ exome AF: 0.790

Gnomad EAS exome AF: 0.869

Gnomad SAS exome AF: 0.634

Gnomad FIN exome AF: 0.793

Gnomad NFE exome AF: 0.813

Gnomad OTH exome AF: 0.809

GnomAD4 exome AF: 0.809 AC: 1178158 AN: 1455960 Hom.: 478986 Cov.: 39 AF XY: 0.803 AC XY: 581636 AN XY: 724320

Gnomad4 AFR exome AF: 0.780

Gnomad4 AMR exome AF: 0.902

Gnomad4 ASJ exome AF: 0.798

Gnomad4 EAS exome AF: 0.912

Gnomad4 SAS exome AF: 0.631

Gnomad4 FIN exome AF: 0.793

Gnomad4 NFE exome AF: 0.818

Gnomad4 OTH exome AF: 0.805

GnomAD4 genome AF: 0.808 AC: 122899 AN: 152150 Hom.: 49786 Cov.: 33 AF XY: 0.806 AC XY: 59909 AN XY: 74368

Gnomad4 AFR AF: 0.783

Gnomad4 AMR AF: 0.872

Gnomad4 ASJ AF: 0.796

Gnomad4 EAS AF: 0.883

Gnomad4 SAS AF: 0.641

Gnomad4 FIN AF: 0.788

Gnomad4 NFE AF: 0.817

Gnomad4 OTH AF: 0.836

Alfa AF: 0.815 Hom.: 29482

Bravo AF: 0.818

Asia WGS AF: 0.786 AC: 2732 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 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. -

Myosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Ullrich congenital muscular dystrophy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.1
DANN	Benign	0.72
La Branchor		0.58
BranchPoint Hunter		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2839113; hg19: chr21-47545155;