rs117038107

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004370.6(COL12A1):c.6590C>T(p.Thr2197Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,610,238 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 5 hom., cov: 32)

Exomes 𝑓: 0.011 ( 101 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.731

Publications

12 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=0.0041609406).

BP6

Variant 6-75125144-G-A is Benign according to our data. Variant chr6-75125144-G-A is described in ClinVar as Benign. ClinVar VariationId is 475889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00772 (1175/152224) while in subpopulation NFE AF = 0.0102 (693/67992). AF 95% confidence interval is 0.00956. There are 5 homozygotes in GnomAd4. There are 578 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6 link	c.6590C>T	p.Thr2197Ile	missense_variant	Exon 40 of 66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL12A1	ENST00000322507.13 link	c.6590C>T	p.Thr2197Ile	missense_variant	Exon 40 of 66	1	NM_004370.6	ENSP00000325146.8
COL12A1	ENST00000345356.10 link	c.3098C>T	p.Thr1033Ile	missense_variant	Exon 25 of 51	1		ENSP00000305147.9
COL12A1	ENST00000483888.6 link	c.6590C>T	p.Thr2197Ile	missense_variant	Exon 40 of 65	5		ENSP00000421216.1
COL12A1	ENST00000416123.6 link	c.6590C>T	p.Thr2197Ile	missense_variant	Exon 39 of 63	5		ENSP00000412864.2

Frequencies

GnomAD3 genomes

AF:

0.00773

AC:

1176

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00952

Gnomad FIN

AF:

0.0207

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00868

AC:

2138

AN:

246304

AF XY:

0.00916

show subpopulations

Gnomad AFR exome

AF:

0.00143

Gnomad AMR exome

AF:

0.00321

Gnomad ASJ exome

AF:

0.00291

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0202

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00726

GnomAD4 exome

AF:

0.0108

AC:

15689

AN:

1458014

Hom.:

101

Cov.:

AF XY:

0.0108

AC XY:

7813

AN XY:

725210

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

33330

American (AMR)

AF:

0.00352

AC:

156

AN:

44326

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

26026

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39534

South Asian (SAS)

AF:

0.0101

AC:

863

AN:

85450

European-Finnish (FIN)

AF:

0.0197

AC:

1051

AN:

53324

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0116

AC:

12821

AN:

1110032

Other (OTH)

AF:

0.0106

AC:

640

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

743

1486

2228

2971

3714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

516

1032

1548

2064

2580

<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:

0.00772

AC:

1175

AN:

152224

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

578

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00202

AC:

AN:

41540

American (AMR)

AF:

0.00608

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00932

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0207

AC:

220

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0102

AC:

693

AN:

67992

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

113

169

226

282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00844

Hom.:

Bravo

AF:

0.00637

TwinsUK

AF:

0.0111

AC:

ESP6500AA

AF:

0.00263

AC:

ESP6500EA

AF:

0.0119

AC:

ExAC

AF:

0.00904

AC:

1093

Asia WGS

AF:

0.00376

AC:

AN:

3476

EpiCase

AF:

0.0102

EpiControl

AF:

0.0105

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL12A1: BP4, BS1, BS2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 12, 2019

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

T;T;.;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.14

LIST_S2

Benign

0.85

T;T;T;T;T

MetaRNN

Benign

0.0042

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

.;L;.;L;.

PhyloP100

0.73

PrimateAI

Benign

0.47

PROVEAN

Benign

0.0

.;N;N;N;N

Sift

Pathogenic

0.0

.;T;T;T;T

Sift4G

Benign

0.30

T;T;T;T;T

Vest4

0.13

ClinPred

0.0035

GERP RS

3.4

Varity_R

0.082

gMVP

0.38

Mutation Taster

=97/3

polymorphism

(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