6-75138453-C-T

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.5225G>A(p.Arg1742His) variant causes a missense change. The variant allele was found at a frequency of 0.0036 in 1,613,066 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1742C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 85 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 66 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.73

Publications

4 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=0.00811252).

BP6

Variant 6-75138453-C-T is Benign according to our data. Variant chr6-75138453-C-T is described in ClinVar as Benign. ClinVar VariationId is 259337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6 link	c.5225G>A	p.Arg1742His	missense_variant	Exon 29 of 66	ENST00000322507.13	NP_004361.3	Q99715-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13 link	c.5225G>A	p.Arg1742His	missense_variant	Exon 29 of 66	1	NM_004370.6	ENSP00000325146.8		Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.0187

AC:

2845

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0642

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00844

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.00509

AC:

1263

AN:

247950

AF XY:

0.00387

show subpopulations

Gnomad AFR exome

AF:

0.0670

Gnomad AMR exome

AF:

0.00462

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000511

Gnomad NFE exome

AF:

0.000320

Gnomad OTH exome

AF:

0.00250

GnomAD4 exome

AF:

0.00203

AC:

2964

AN:

1460834

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1276

AN XY:

726648

show subpopulations

African (AFR)

AF:

0.0665

AC:

2223

AN:

33410

American (AMR)

AF:

0.00527

AC:

235

AN:

44572

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26088

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39664

South Asian (SAS)

AF:

0.000140

AC:

AN:

85932

European-Finnish (FIN)

AF:

0.000375

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000159

AC:

177

AN:

1111650

Other (OTH)

AF:

0.00441

AC:

266

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

132

264

396

528

660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.0187

AC:

2848

AN:

152232

Hom.:

Cov.:

AF XY:

0.0182

AC XY:

1353

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0641

AC:

2661

AN:

41526

American (AMR)

AF:

0.00843

AC:

129

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68012

Other (OTH)

AF:

0.0185

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

134

267

401

534

668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00585

Hom.:

Bravo

AF:

0.0222

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0600

AC:

229

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00568

AC:

687

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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 02, 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

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

T;T;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

D;D;D;D;D

MetaRNN

Benign

0.0081

T;T;T;T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.9

.;M;.;M;.

PhyloP100

4.7

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.5

.;N;N;N;N

REVEL

Uncertain

0.48

Sift

Uncertain

0.0090

.;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

1.0

.;D;D;.;.

Vest4

0.33

MVP

0.76

MPC

0.63

ClinPred

0.027

GERP RS

5.8

Varity_R

0.095

gMVP

0.66

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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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