21-46117958-C-T

Variant names:

• chr21-46117958-C-T
• rs111592472
• NM_001849.4:c.1116+22C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001849.4(COL6A2):​c.1116+22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,602,654 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (31 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0870
• 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, 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: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-46117958-C-T is Benign according to our data. Variant chr21-46117958-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1870/152142) while in subpopulation AFR AF = 0.0407 (1689/41524). AF 95% confidence interval is 0.0391. There are 40 homozygotes in GnomAd4. There are 877 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1116+22C>T		intron_variant	Intron 12 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1116+22C>T		intron_variant	Intron 12 of 27		NP_478054.2
COL6A2	NM_058175.3	c.1116+22C>T		intron_variant	Intron 12 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1116+22C>T		intron_variant	Intron 12 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1116+22C>T		intron_variant	Intron 12 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1116+22C>T		intron_variant	Intron 11 of 26	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1868 AN: 152024 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0407

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00341 AC: 818 AN: 239790 AF XY: 0.00251

Gnomad AFR exome AF: 0.0395

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000471

Gnomad OTH exome AF: 0.00242

GnomAD4 exome AF: 0.00151 AC: 2186 AN: 1450512 Hom.: 31 Cov.: 32 AF XY: 0.00131 AC XY: 942 AN XY: 719852

African (AFR) AF: 0.0400 AC: 1334 AN: 33310

American (AMR) AF: 0.00496 AC: 219 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25792

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39382

South Asian (SAS) AF: 0.000235 AC: 20 AN: 85038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52190

Middle Eastern (MID) AF: 0.00384 AC: 22 AN: 5724

European-Non Finnish (NFE) AF: 0.000321 AC: 355 AN: 1105126

Other (OTH) AF: 0.00388 AC: 232 AN: 59826

GnomAD4 genome AF: 0.0123 AC: 1870 AN: 152142 Hom.: 40 Cov.: 33 AF XY: 0.0118 AC XY: 877 AN XY: 74376

African (AFR) AF: 0.0407 AC: 1689 AN: 41524

American (AMR) AF: 0.00830 AC: 127 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67958

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.00553 Hom.: 2

Bravo AF: 0.0141

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.73
DANN	Benign	0.66
PhyloP100		-0.087
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs111592472; hg19: chr21-47537872;