rs150275851

Variant names:

• chr21-46125327-CG-C
• rs150275851
• NM_001849.4:c.1816+18delG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001849.4(COL6A2):​c.1816+18delG 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
• Publications: 2 publications found

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]

COL6A2 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, SD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 93923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 89 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	NM_001849.4	MANE Select	c.1816+18delG		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1816+18delG		intron	N/A	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.1816+18delG		intron	N/A	NP_478055.2	P12110-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.1816+17delG		intron	N/A	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1816+17delG		intron	N/A	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.2011+17delG		intron	N/A	ENSP00000527157.1

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

GnomAD2 exomes AF: 0.0290 AC: 7126 AN: 245630 AF XY: 0.0295

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 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

African (AFR) AF: 0.00650 AC: 217 AN: 33400

American (AMR) AF: 0.0193 AC: 856 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 471 AN: 25784

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39626

South Asian (SAS) AF: 0.0113 AC: 965 AN: 85594

European-Finnish (FIN) AF: 0.0327 AC: 1699 AN: 52030

Middle Eastern (MID) AF: 0.0327 AC: 188 AN: 5752

European-Non Finnish (NFE) AF: 0.0436 AC: 48336 AN: 1109076

Other (OTH) AF: 0.0340 AC: 2045 AN: 60154

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

African (AFR) AF: 0.00772 AC: 321 AN: 41564

American (AMR) AF: 0.0272 AC: 417 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00891 AC: 43 AN: 4828

European-Finnish (FIN) AF: 0.0271 AC: 288 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0432 AC: 2935 AN: 67994

Other (OTH) AF: 0.0312 AC: 66 AN: 2116

Alfa AF: 0.0346 Hom.: 19

Bravo AF: 0.0269

Asia WGS AF: 0.00549 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs150275851; hg19: chr21-47545241;