rs240736

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.5213T>C(p.Ile1738Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,613,334 control chromosomes in the GnomAD database, including 64,381 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6440 hom., cov: 32)

Exomes 𝑓: 0.28 ( 57941 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.403

Publications

43 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=0.0029047132).

BP6

Variant 6-75138465-A-G is Benign according to our data. Variant chr6-75138465-A-G is described in ClinVar as Benign. ClinVar VariationId is 259336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6 link	c.5213T>C	p.Ile1738Thr	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.5213T>C	p.Ile1738Thr	missense_variant	Exon 29 of 66	1	NM_004370.6	ENSP00000325146.8		Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.290

AC:

44099

AN:

151970

Hom.:

6440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.330

Gnomad AMI

AF:

0.303

Gnomad AMR

AF:

0.295

Gnomad ASJ

AF:

0.297

Gnomad EAS

AF:

0.144

Gnomad SAS

AF:

0.232

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.288

Gnomad OTH

AF:

0.297

GnomAD2 exomes

AF:

0.264

AC:

65633

AN:

248634

AF XY:

0.263

show subpopulations

Gnomad AFR exome

AF:

0.330

Gnomad AMR exome

AF:

0.277

Gnomad ASJ exome

AF:

0.278

Gnomad EAS exome

AF:

0.148

Gnomad FIN exome

AF:

0.229

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.272

GnomAD4 exome

AF:

0.279

AC:

407739

AN:

1461246

Hom.:

57941

Cov.:

AF XY:

0.277

AC XY:

201551

AN XY:

726876

show subpopulations

African (AFR)

AF:

0.335

AC:

11200

AN:

33458

American (AMR)

AF:

0.282

AC:

12594

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

7337

AN:

26122

East Asian (EAS)

AF:

0.142

AC:

5622

AN:

39676

South Asian (SAS)

AF:

0.231

AC:

19905

AN:

86144

European-Finnish (FIN)

AF:

0.232

AC:

12376

AN:

53400

Middle Eastern (MID)

AF:

0.296

AC:

1704

AN:

5764

European-Non Finnish (NFE)

AF:

0.288

AC:

320567

AN:

1111630

Other (OTH)

AF:

0.272

AC:

16434

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

14930

29860

44790

59720

74650

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10640

21280

31920

42560

53200

<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:

0.290

AC:

44110

AN:

152088

Hom.:

6440

Cov.:

AF XY:

0.286

AC XY:

21231

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.330

AC:

13672

AN:

41450

American (AMR)

AF:

0.295

AC:

4504

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

1031

AN:

3468

East Asian (EAS)

AF:

0.145

AC:

749

AN:

5178

South Asian (SAS)

AF:

0.231

AC:

1110

AN:

4814

European-Finnish (FIN)

AF:

0.231

AC:

2445

AN:

10598

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.288

AC:

19610

AN:

67984

Other (OTH)

AF:

0.294

AC:

621

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1629

3258

4887

6516

8145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

430

860

1290

1720

2150

<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:

0.285

Hom.:

28672

Bravo

AF:

0.296

TwinsUK

AF:

0.305

AC:

1132

ALSPAC

AF:

0.267

AC:

1029

ESP6500AA

AF:

0.308

AC:

1179

ESP6500EA

AF:

0.285

AC:

2364

ExAC

AF:

0.264

AC:

31933

Asia WGS

AF:

0.197

AC:

690

AN:

3476

EpiCase

AF:

0.287

EpiControl

AF:

0.291

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, Amsterdam University 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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Bethlem myopathy 2

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 05, 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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ullrich congenital muscular dystrophy 2

Benign:1

Jul 22, 2021

Genome-Nilou Lab

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

0.053

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.91

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.0026

T;T;.;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.83

T;T;T;T;T

MetaRNN

Benign

0.0029

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.20

.;N;.;N;.

PhyloP100

0.40

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.43

.;N;N;N;N

REVEL

Benign

0.29

Sift

Benign

0.57

.;T;T;T;T

Sift4G

Benign

0.64

T;T;T;T;T

Polyphen

0.0

.;B;B;.;.

Vest4

0.015

MPC

0.15

ClinPred

0.0080

GERP RS

-12

Varity_R

0.028

gMVP

0.37

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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