rs200408101

Positions:

chr6-75113256-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_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. 12/21 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL12A1. . Gene score misZ 2.106 (greater than the threshold 3.09). Trascript score misZ 3.5535 (greater than threshold 3.09). GenCC has associacion of gene with Bethlem myopathy, Bethlem myopathy 2, Ullrich congenital muscular dystrophy 2, Ullrich congenital muscular dystrophy.

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 id is 259348.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}.

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6 linkuse as main transcript	c.7898T>C	p.Val2633Ala	missense_variant	51/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13 linkuse as main transcript	c.7898T>C	p.Val2633Ala	missense_variant	51/66	1	NM_004370.6	P4	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

GnomAD3 exomes

AF:

0.000347

AC:

AN:

218968

Hom.:

AF XY:

0.000317

AC XY:

AN XY:

120032

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 SAS exome

AF:

0.000115

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

Gnomad4 AFR exome

AF:

0.00526

Gnomad4 AMR exome

AF:

0.000440

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000434

Gnomad4 SAS exome

AF:

0.000208

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000688

Gnomad4 OTH exome

AF:

0.000931

GnomAD4 genome

AF:

0.00107

AC:

162

AN:

151886

Hom.:

Cov.:

AF XY:

0.000956

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.00303

Gnomad4 AMR

AF:

0.000788

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000238

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

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2021	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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	COL12A1: BP4 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

See cases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jan 03, 2020

ACMG classification criteria: BS1, BP4 -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

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

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;.;.

MutationTaster

Benign

0.89

D;D;D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over