rs41266761

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004370.6(COL12A1):c.9083G>A(p.Arg3028His) variant causes a missense change. The variant allele was found at a frequency of 0.00566 in 1,610,232 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3028C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0046 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 41 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 5.82

Publications

8 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011844844).

BP6

Variant 6-75087675-C-T is Benign according to our data. Variant chr6-75087675-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259356.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00461 (702/152248) while in subpopulation NFE AF = 0.0076 (517/68016). AF 95% confidence interval is 0.00706. There are 2 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6 link	c.9083G>A	p.Arg3028His	missense_variant	Exon 65 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.9083G>A	p.Arg3028His	missense_variant	Exon 65 of 66	1	NM_004370.6	ENSP00000325146.8		Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.00462

AC:

703

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00760

Gnomad OTH

AF:

0.00384

GnomAD2 exomes

AF:

0.00407

AC:

996

AN:

244726

AF XY:

0.00413

show subpopulations

Gnomad AFR exome

AF:

0.00176

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00363

Gnomad NFE exome

AF:

0.00701

Gnomad OTH exome

AF:

0.00355

GnomAD4 exome

AF:

0.00577

AC:

8412

AN:

1457984

Hom.:

Cov.:

AF XY:

0.00564

AC XY:

4088

AN XY:

725302

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

33168

American (AMR)

AF:

0.00173

AC:

AN:

43468

Ashkenazi Jewish (ASJ)

AF:

0.000270

AC:

AN:

25944

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39572

South Asian (SAS)

AF:

0.000736

AC:

AN:

85640

European-Finnish (FIN)

AF:

0.00354

AC:

189

AN:

53384

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00698

AC:

7752

AN:

1110820

Other (OTH)

AF:

0.00471

AC:

284

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

439

878

1318

1757

2196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00461

AC:

702

AN:

152248

Hom.:

Cov.:

AF XY:

0.00443

AC XY:

330

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

41540

American (AMR)

AF:

0.00353

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00760

AC:

517

AN:

68016

Other (OTH)

AF:

0.00380

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00486

Hom.:

Bravo

AF:

0.00445

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00187

AC:

ESP6500EA

AF:

0.00709

AC:

ExAC

AF:

0.00438

AC:

529

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00494

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL12A1: BS2 -

Sep 14, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Apr 29, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

- -

Dec 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL12A1 c.9083G>A (p.Arg3028His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 244726 control chromosomes, predominantly at a frequency of 0.007 within the Non-Finnish European subpopulation in the gnomAD database, including 8 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL12A1 causing Ullrich congenital muscular dystrophy 2 phenotype (0.0035). To our knowledge, no occurrence of c.9083G>A in individuals affected with Ullrich congenital muscular dystrophy 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 259356). Based on the evidence outlined above, the variant was classified as benign. -

Inborn genetic diseases

Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.9083G>A (p.R3028H) alteration is located in exon 65 (coding exon 64) of the COL12A1 gene. This alteration results from a G to A substitution at nucleotide position 9083, causing the arginine (R) at amino acid position 3028 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

- -

Ullrich congenital muscular dystrophy 2

Benign:1

May 28, 2019

Mendelics

Significance:Likely 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

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.014

.;T;T;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.012

T;T;T;T;T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.6

.;.;L;.;.;.

PhyloP100

5.8

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.83

N;.;N;N;N;N

REVEL

Uncertain

0.53

Sift

Benign

0.90

T;.;T;T;T;T

Sift4G

Benign

0.14

T;T;T;T;T;T

Polyphen

1.0

.;.;D;D;.;.

Vest4

0.51, 0.55, 0.56, 0.63, 0.52

MVP

0.79

MPC

1.5

ClinPred

0.020

GERP RS

5.8

Varity_R

0.15

gMVP

0.47

Mutation Taster

=87/13

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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rs41266761

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