21-46120507-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001849.4(COL6A2):c.1333-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,512,874 control chromosomes in the GnomAD database, including 37,201 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2760 hom., cov: 34)

Exomes 𝑓: 0.22 ( 34441 hom. )

Consequence

COL6A2
NM_001849.4 splice_region, intron

Scores

Splicing: ADA: 0.0001797

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.804

Publications

7 publications found

Variant links:

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

COL6A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 21-46120507-T-C is Benign according to our data. Variant chr21-46120507-T-C is described in ClinVar as Benign. ClinVar VariationId is 93906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4 link	c.1333-8T>C	splice_region_variant, intron_variant	Intron 15 of 27	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 link	c.1333-8T>C	splice_region_variant, intron_variant	Intron 15 of 27		NP_478054.2	P12110-2
COL6A2	NM_058175.3 link	c.1333-8T>C	splice_region_variant, intron_variant	Intron 15 of 27		NP_478055.2	P12110-3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL6A2	ENST00000300527.9 link	c.1333-8T>C	splice_region_variant, intron_variant	Intron 15 of 27	1	NM_001849.4	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6 link	c.1333-8T>C	splice_region_variant, intron_variant	Intron 15 of 27	5		ENSP00000380870.1	P12110-2
COL6A2	ENST00000409416.6 link	c.1333-8T>C	splice_region_variant, intron_variant	Intron 14 of 26	5		ENSP00000387115.1	P12110-3
COL6A2	ENST00000413758.1 link	c.-53T>C	upstream_gene_variant		3		ENSP00000395751.1	H7C0M5

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27138

AN:

151980

Hom.:

2759

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.169

Gnomad ASJ

AF:

0.186

Gnomad EAS

AF:

0.307

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.0754

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.219

Gnomad OTH

AF:

0.213

GnomAD2 exomes

AF:

0.179

AC:

20432

AN:

114234

AF XY:

0.181

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.155

Gnomad ASJ exome

AF:

0.178

Gnomad EAS exome

AF:

0.291

Gnomad FIN exome

AF:

0.0747

Gnomad NFE exome

AF:

0.219

Gnomad OTH exome

AF:

0.190

GnomAD4 exome

AF:

0.217

AC:

295954

AN:

1360774

Hom.:

34441

Cov.:

AF XY:

0.216

AC XY:

144602

AN XY:

670540

show subpopulations

African (AFR)

AF:

0.115

AC:

3391

AN:

29522

American (AMR)

AF:

0.154

AC:

4211

AN:

27320

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

4286

AN:

22882

East Asian (EAS)

AF:

0.385

AC:

13353

AN:

34682

South Asian (SAS)

AF:

0.151

AC:

11261

AN:

74554

European-Finnish (FIN)

AF:

0.0821

AC:

3865

AN:

47068

Middle Eastern (MID)

AF:

0.233

AC:

1132

AN:

4856

European-Non Finnish (NFE)

AF:

0.228

AC:

242524

AN:

1063930

Other (OTH)

AF:

0.213

AC:

11931

AN:

55960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

10234

20468

30703

40937

51171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8464

16928

25392

33856

42320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.178

AC:

27144

AN:

152100

Hom.:

2760

Cov.:

AF XY:

0.173

AC XY:

12849

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.125

AC:

5189

AN:

41524

American (AMR)

AF:

0.169

AC:

2584

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

646

AN:

3468

East Asian (EAS)

AF:

0.307

AC:

1586

AN:

5162

South Asian (SAS)

AF:

0.163

AC:

786

AN:

4814

European-Finnish (FIN)

AF:

0.0754

AC:

800

AN:

10614

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.220

AC:

14907

AN:

67910

Other (OTH)

AF:

0.213

AC:

449

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1171

2342

3512

4683

5854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.189

Hom.:

963

Bravo

AF:

0.185

Asia WGS

AF:

0.220

AC:

767

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jan 28, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 07, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 19, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myosclerosis

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bethlem myopathy 1A

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Collagen 6-related myopathy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.4

(source)

DANN

Benign

0.73

PhyloP100

-0.80

PromoterAI

0.0022

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00018

dbscSNV1_RF

Benign

0.016

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over