rs149172490

Positions:

• chr21-46129383-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001849.4(COL6A2):​c.2462-2571C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00744 in 1,613,024 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (52 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.213

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 21-46129383-C-T is Benign according to our data. Variant chr21-46129383-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46129383-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_058174.3	c.2649C>T	p.Phe883=	synonymous_variant	28/28	ENST00000397763.6
COL6A2	NM_001849.4	c.2462-2571C>T		intron_variant		ENST00000300527.9
COL6A2	NM_058175.3	c.*455C>T		3_prime_UTR_variant	28/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000397763.6	c.2649C>T	p.Phe883=	synonymous_variant	28/28	5	NM_058174.3
COL6A2	ENST00000300527.9	c.2462-2571C>T		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000409416.6	c.*455C>T		3_prime_UTR_variant	27/27	5

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 779 AN: 152240 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00902

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00517 AC: 1293 AN: 250208 Hom.: 7 AF XY: 0.00508 AC XY: 688 AN XY: 135510

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00423

Gnomad ASJ exome AF: 0.00429

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00887

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00768 AC: 11221 AN: 1460666 Hom.: 52 Cov.: 31 AF XY: 0.00748 AC XY: 5435 AN XY: 726662

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.00502

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00179

Gnomad4 NFE exome AF: 0.00935

Gnomad4 OTH exome AF: 0.00547

GnomAD4 genome AF: 0.00511 AC: 779 AN: 152358 Hom.: 6 Cov.: 33 AF XY: 0.00471 AC XY: 351 AN XY: 74506

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00903

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00755 Hom.: 5

Bravo AF: 0.00526

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00853

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	COL6A2: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2020	- -

Ullrich congenital muscular dystrophy 1A;C1850671:Myosclerosis;CN029274:Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 24, 2021

- -

COL6A2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.75

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: rs149172490; hg19: chr21-47549297; COSMIC: COSV56015837; COSMIC: COSV56015837;