6-75087586-C-T

Position:

chr6-75087586-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_004370.6(COL12A1):c.9172G>A(p.Gly3058Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,613,022 control chromosomes in the GnomAD database, including 468,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 40316 hom., cov: 30)

Exomes 𝑓: 0.76 ( 427763 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.57

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 -19 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=3.371506E-6).

BP6

Variant 6-75087586-C-T is Benign according to our data. Variant chr6-75087586-C-T is described in ClinVar as [Benign]. Clinvar id is 259358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75087586-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6 link	c.9172G>A	p.Gly3058Ser	missense_variant	65/66	ENST00000322507.13	NP_004361.3	Q99715-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13 link	c.9172G>A	p.Gly3058Ser	missense_variant	65/66	1	NM_004370.6	ENSP00000325146.8		Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.726

AC:

110227

AN:

151856

Hom.:

40303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.656

Gnomad AMI

AF:

0.618

Gnomad AMR

AF:

0.764

Gnomad ASJ

AF:

0.762

Gnomad EAS

AF:

0.664

Gnomad SAS

AF:

0.680

Gnomad FIN

AF:

0.656

Gnomad MID

AF:

0.687

Gnomad NFE

AF:

0.778

Gnomad OTH

AF:

0.742

GnomAD3 exomes

AF:

0.747

AC:

185847

AN:

248804

Hom.:

70040

AF XY:

0.741

AC XY:

100056

AN XY:

135046

show subpopulations

Gnomad AFR exome

AF:

0.657

Gnomad AMR exome

AF:

0.837

Gnomad ASJ exome

AF:

0.761

Gnomad EAS exome

AF:

0.662

Gnomad SAS exome

AF:

0.670

Gnomad FIN exome

AF:

0.670

Gnomad NFE exome

AF:

0.779

Gnomad OTH exome

AF:

0.749

GnomAD4 exome

AF:

0.764

AC:

1115636

AN:

1461048

Hom.:

427763

Cov.:

AF XY:

0.761

AC XY:

552931

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.647

Gnomad4 AMR exome

AF:

0.826

Gnomad4 ASJ exome

AF:

0.767

Gnomad4 EAS exome

AF:

0.661

Gnomad4 SAS exome

AF:

0.671

Gnomad4 FIN exome

AF:

0.677

Gnomad4 NFE exome

AF:

0.781

Gnomad4 OTH exome

AF:

0.749

GnomAD4 genome

AF:

0.726

AC:

110286

AN:

151974

Hom.:

40316

Cov.:

AF XY:

0.718

AC XY:

53347

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.656

Gnomad4 AMR

AF:

0.764

Gnomad4 ASJ

AF:

0.762

Gnomad4 EAS

AF:

0.664

Gnomad4 SAS

AF:

0.680

Gnomad4 FIN

AF:

0.656

Gnomad4 NFE

AF:

0.777

Gnomad4 OTH

AF:

0.744

Alfa

AF:

0.767

Hom.:

108079

Bravo

AF:

0.734

TwinsUK

AF:

0.786

AC:

2914

ALSPAC

AF:

0.784

AC:

3020

ESP6500AA

AF:

0.659

AC:

2515

ESP6500EA

AF:

0.784

AC:

6486

ExAC

AF:

0.745

AC:

89988

Asia WGS

AF:

0.668

AC:

2327

AN:

3478

EpiCase

AF:

0.773

EpiControl

AF:

0.771

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Bethlem myopathy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

This variant is associated with the following publications: (PMID: 16741161) -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Ullrich congenital muscular dystrophy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

.;T;T;.;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

T;T;T;T;T;T

MetaRNN

Benign

0.0000034

T;T;T;T;T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

2.0

.;.;M;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.5

N;.;N;N;N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.023

D;.;T;D;D;T

Sift4G

Benign

0.13

T;D;D;D;D;D

Polyphen

1.0

.;.;D;D;.;.

Vest4

0.44, 0.24, 0.56, 0.48, 0.45

MPC

1.4

ClinPred

0.016

GERP RS

5.8

Varity_R

0.26

gMVP

0.76

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