rs35523808

Variant names:

Variant summary

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

The NM_004370.6(COL12A1):c.6479A>T(p.Glu2160Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0437 in 1,607,394 control chromosomes in the GnomAD database, including 1,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 135 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1729 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.36

Publications

18 publications found

Variant links:

Genes affected

COL12A1 (HGNC:2188): (collagen type XII alpha 1 chain) This gene encodes the alpha chain of type XII collagen, a member of the FACIT (fibril-associated collagens with interrupted triple helices) collagen family. Type XII collagen is a homotrimer found in association with type I collagen, an association that is thought to modify the interactions between collagen I fibrils and the surrounding matrix. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

COL12A1 Gene-Disease associations (from GenCC):

Bethlem myopathy 2
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Bethlem myopathy 2
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp
Ullrich congenital muscular dystrophy 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL12A1 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 (MetaRNN=0.003599733).

BP6

Variant 6-75125255-T-A is Benign according to our data. Variant chr6-75125255-T-A is described in ClinVar as Benign. ClinVar VariationId is 259344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6 link	c.6479A>T	p.Glu2160Val	missense_variant	Exon 40 of 66	ENST00000322507.13	NP_004361.3	Q99715-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL12A1	ENST00000322507.13 link	c.6479A>T	p.Glu2160Val	missense_variant	Exon 40 of 66	1	NM_004370.6	ENSP00000325146.8	Q99715-1
COL12A1	ENST00000345356.10 link	c.2987A>T	p.Glu996Val	missense_variant	Exon 25 of 51	1		ENSP00000305147.9	Q99715-2
COL12A1	ENST00000483888.6 link	c.6479A>T	p.Glu2160Val	missense_variant	Exon 40 of 65	5		ENSP00000421216.1	D6RGG3
COL12A1	ENST00000416123.6 link	c.6479A>T	p.Glu2160Val	missense_variant	Exon 39 of 63	5		ENSP00000412864.2	Q99715-4

Frequencies

GnomAD3 genomes

AF:

0.0344

AC:

5235

AN:

152082

Hom.:

134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00847

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0242

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.0574

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0537

Gnomad OTH

AF:

0.0340

GnomAD2 exomes

AF:

0.0343

AC:

8376

AN:

243970

AF XY:

0.0348

show subpopulations

Gnomad AFR exome

AF:

0.00711

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0332

Gnomad EAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.0563

Gnomad NFE exome

AF:

0.0511

Gnomad OTH exome

AF:

0.0346

GnomAD4 exome

AF:

0.0446

AC:

64952

AN:

1455194

Hom.:

1729

Cov.:

AF XY:

0.0438

AC XY:

31702

AN XY:

723574

show subpopulations

African (AFR)

AF:

0.00704

AC:

234

AN:

33244

American (AMR)

AF:

0.0204

AC:

896

AN:

43932

Ashkenazi Jewish (ASJ)

AF:

0.0299

AC:

774

AN:

25900

East Asian (EAS)

AF:

0.000101

AC:

AN:

39446

South Asian (SAS)

AF:

0.00701

AC:

594

AN:

84734

European-Finnish (FIN)

AF:

0.0574

AC:

3057

AN:

53282

Middle Eastern (MID)

AF:

0.0277

AC:

159

AN:

5746

European-Non Finnish (NFE)

AF:

0.0513

AC:

56868

AN:

1108772

Other (OTH)

AF:

0.0393

AC:

2366

AN:

60138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

2774

5548

8321

11095

13869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2024

4048

6072

8096

10120

<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:

0.0344

AC:

5233

AN:

152200

Hom.:

135

Cov.:

AF XY:

0.0337

AC XY:

2511

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00845

AC:

351

AN:

41538

American (AMR)

AF:

0.0241

AC:

369

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00704

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0574

AC:

608

AN:

10600

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0537

AC:

3651

AN:

67984

Other (OTH)

AF:

0.0336

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

262

523

785

1046

1308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0471

Hom.:

140

Bravo

AF:

0.0312

TwinsUK

AF:

0.0494

AC:

183

ALSPAC

AF:

0.0439

AC:

169

ESP6500AA

AF:

0.00924

AC:

ESP6500EA

AF:

0.0474

AC:

390

ExAC

AF:

0.0334

AC:

4037

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0503

EpiControl

AF:

0.0510

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.080

T;T;.;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D

MetaRNN

Benign

0.0036

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

.;L;.;L;.

PhyloP100

7.4

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.0

.;D;D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0020

.;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;D;D;.;.

Vest4

0.54

MPC

1.5

ClinPred

0.0069

GERP RS

5.2

Varity_R

0.63

gMVP

0.70

Mutation Taster

=88/12

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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