rs2276101

Positions:

• chr21-46125432-C-T

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.1817-33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.052 in 1,611,024 control chromosomes in the GnomAD database, including 5,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (616 hom., cov: 33)
  • Exomes 𝑓: 0.050 (5043 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.74

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 (MetaRNN=0.004430741).
• BP6: Variant 21-46125432-C-T is Benign according to our data. Variant chr21-46125432-C-T is described in ClinVar as [Benign]. Clinvar id is 93924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46125432-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.1817-33C>T		intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.1817-33C>T		intron_variant		ENST00000397763.6
COL6A2	NM_058175.3	c.1817-33C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.1817-33C>T		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.1817-33C>T		intron_variant		5	NM_058174.3
COL6A2	ENST00000413758.1	c.455C>T	p.Pro152Leu	missense_variant	10/11	3
COL6A2	ENST00000409416.6	c.1817-33C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0663 AC: 10059 AN: 151834 Hom.: 614 Cov.: 33

Gnomad AFR AF: 0.0858

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0760

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0824

GnomAD3 exomes AF: 0.0753 AC: 18789 AN: 249494 Hom.: 1583 AF XY: 0.0724 AC XY: 9797 AN XY: 135312

Gnomad AFR exome AF: 0.0908

Gnomad AMR exome AF: 0.0896

Gnomad ASJ exome AF: 0.0347

Gnomad EAS exome AF: 0.339

Gnomad SAS exome AF: 0.0820

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.0379

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0505 AC: 73631 AN: 1459070 Hom.: 5043 Cov.: 37 AF XY: 0.0512 AC XY: 37190 AN XY: 725804

Gnomad4 AFR exome AF: 0.0864

Gnomad4 AMR exome AF: 0.0894

Gnomad4 ASJ exome AF: 0.0368

Gnomad4 EAS exome AF: 0.408

Gnomad4 SAS exome AF: 0.0788

Gnomad4 FIN exome AF: 0.0253

Gnomad4 NFE exome AF: 0.0338

Gnomad4 OTH exome AF: 0.0591

GnomAD4 genome AF: 0.0662 AC: 10063 AN: 151954 Hom.: 616 Cov.: 33 AF XY: 0.0682 AC XY: 5066 AN XY: 74304

Gnomad4 AFR AF: 0.0856

Gnomad4 AMR AF: 0.0759

Gnomad4 ASJ AF: 0.0401

Gnomad4 EAS AF: 0.348

Gnomad4 SAS AF: 0.0924

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.0361

Gnomad4 OTH AF: 0.0839

Alfa AF: 0.0448 Hom.: 77

Bravo AF: 0.0731

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0374 AC: 144

ESP6500AA AF: 0.0867 AC: 382

ESP6500EA AF: 0.0388 AC: 334

ExAC AF: 0.0751 AC: 9111

Asia WGS AF: 0.169 AC: 587 AN: 3478

EpiCase AF: 0.0412

EpiControl AF: 0.0389

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 16, 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_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.057
DANN	Benign	0.68
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.096
Sift	Benign	0.13	T
Sift4G	Benign	0.13	T
ClinPred		0.0069	T
GERP RS		-3.5

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: rs2276101; hg19: chr21-47545346; COSMIC: COSV56014201;