rs200408101

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.7898T>C(p.Val2633Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000326 in 1,565,532 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 3 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 3.85

Publications

1 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=0.009590089).

BP6

Variant 6-75113256-A-G is Benign according to our data. Variant chr6-75113256-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259348.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00107 (162/151886) while in subpopulation AFR AF = 0.00303 (126/41536). AF 95% confidence interval is 0.0026. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL12A1	NM_004370.6 link	c.7898T>C	p.Val2633Ala	missense_variant	Exon 51 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.7898T>C	p.Val2633Ala	missense_variant	Exon 51 of 66	1	NM_004370.6	ENSP00000325146.8		Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

160

AN:

151768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000789

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000347

AC:

AN:

218968

AF XY:

0.000317

show subpopulations

Gnomad AFR exome

AF:

0.00279

Gnomad AMR exome

AF:

0.000285

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000863

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000108

Gnomad OTH exome

AF:

0.000975

GnomAD4 exome

AF:

0.000247

AC:

349

AN:

1413646

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

165

AN XY:

702086

show subpopulations

African (AFR)

AF:

0.00526

AC:

163

AN:

30972

American (AMR)

AF:

0.000440

AC:

AN:

38624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25112

East Asian (EAS)

AF:

0.000434

AC:

AN:

36904

South Asian (SAS)

AF:

0.000208

AC:

AN:

77012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50632

Middle Eastern (MID)

AF:

0.00142

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.0000688

AC:

AN:

1090748

Other (OTH)

AF:

0.000931

AC:

AN:

58008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00107

AC:

162

AN:

151886

Hom.:

Cov.:

AF XY:

0.000956

AC XY:

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.00303

AC:

126

AN:

41536

American (AMR)

AF:

0.000788

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67746

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000494

Hom.:

Bravo

AF:

0.00108

ESP6500AA

AF:

0.00193

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000439

AC:

Asia WGS

AF:

0.00380

AC:

AN:

3440

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL12A1: BP4 -

Aug 04, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Internal segregation studies show this variant has been inherited from reportedly unaffected parents; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 259348; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

See cases

Benign:1

Jan 03, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: BS1, BP4 -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

0.20

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.071

.;T;D;.;.;.;T

Eigen

Benign

-0.084

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;D;D;D;D;D;D

M_CAP

Benign

0.0076

MetaRNN

Benign

0.0096

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

.;.;L;.;L;.;.

PhyloP100

3.9

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.0

D;.;D;D;D;D;D

REVEL

Benign

0.046

Sift

Benign

0.14

T;.;T;T;T;T;T

Sift4G

Benign

0.16

T;T;T;T;T;T;T

Polyphen

0.0020, 0.013

.;.;B;B;.;.;.

Vest4

0.12, 0.32, 0.39, 0.33, 0.27

MVP

0.33

MPC

0.62

ClinPred

0.015

GERP RS

5.6

Varity_R

0.14

gMVP

0.50

Mutation Taster

=83/17

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