rs150275851

chr21-46125327-CG-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001849.4(COL6A2):c.1816+18del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,608,120 control chromosomes in the GnomAD database, including 1,300 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (89 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1211 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.12

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 21-46125327-CG-C is Benign according to our data. Variant chr21-46125327-CG-C is described in ClinVar as [Likely_benign]. Clinvar id is 93923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46125327-CG-C is described in Lovd as [Benign]. Variant chr21-46125327-CG-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0276 (4200/152268) while in subpopulation NFE AF= 0.0432 (2935/67994). AF 95% confidence interval is 0.0419. There are 89 homozygotes in gnomad4. There are 1973 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 89 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.1816+18del		intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.1816+18del		intron_variant		ENST00000397763.6
COL6A2	NM_058175.3	c.1816+18del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.1816+18del		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.1816+18del		intron_variant		5	NM_058174.3
COL6A2	ENST00000409416.6	c.1816+18del		intron_variant		5
COL6A2	ENST00000413758.1	c.439+18del		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4202 AN: 152150 Hom.: 89 Cov.: 33

Gnomad AFR AF: 0.00775

Gnomad AMI AF: 0.0815

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0432

Gnomad OTH AF: 0.0315

GnomAD3 exomes AF: 0.0290 AC: 7126 AN: 245630 Hom.: 153 AF XY: 0.0295 AC XY: 3929 AN XY: 133222

Gnomad AFR exome AF: 0.00660

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.0321

Gnomad NFE exome AF: 0.0450

Gnomad OTH exome AF: 0.0362

GnomAD4 exome AF: 0.0376 AC: 54779 AN: 1455852 Hom.: 1211 Cov.: 36 AF XY: 0.0370 AC XY: 26761 AN XY: 723788

Gnomad4 AFR exome AF: 0.00650

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.0327

Gnomad4 NFE exome AF: 0.0436

Gnomad4 OTH exome AF: 0.0340

GnomAD4 genome AF: 0.0276 AC: 4200 AN: 152268 Hom.: 89 Cov.: 33 AF XY: 0.0265 AC XY: 1973 AN XY: 74454

Gnomad4 AFR AF: 0.00772

Gnomad4 AMR AF: 0.0272

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.0432

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0346 Hom.: 19

Bravo AF: 0.0269

Asia WGS AF: 0.00549 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2016	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	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs150275851; hg19: chr21-47545241;