rs41266761

Positions:

chr6-75087675-C-T

Variant summary

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

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:10

Conservation

PhyloP100: 5.82

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:

COL12A1 (HGNC:):

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=0.011844844).

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 Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=2}. Variant chr6-75087675-C-T is described in Lovd as [Likely_benign]. Variant chr6-75087675-C-T is described in Lovd as [Benign].

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

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6 linkuse as main transcript	c.9083G>A	p.Arg3028His	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 linkuse as main transcript	c.9083G>A	p.Arg3028His	missense_variant	65/66	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

GnomAD3 exomes

AF:

0.00407

AC:

996

AN:

244726

Hom.:

AF XY:

0.00413

AC XY:

549

AN XY:

132950

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 SAS exome

AF:

0.000804

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

Gnomad4 AFR exome

AF:

0.00103

Gnomad4 AMR exome

AF:

0.00173

Gnomad4 ASJ exome

AF:

0.000270

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000736

Gnomad4 FIN exome

AF:

0.00354

Gnomad4 NFE exome

AF:

0.00698

Gnomad4 OTH exome

AF:

0.00471

GnomAD4 genome

AF:

0.00461

AC:

702

AN:

152248

Hom.:

Cov.:

AF XY:

0.00443

AC XY:

330

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00173

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00760

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.00613

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:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	COL12A1: BS2 -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 29, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Ullrich congenital muscular dystrophy 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

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;.;.;.

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

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