rs34369939

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004370.6(COL12A1):c.8237T>C(p.Val2746Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,766 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0091 ( 12 hom., cov: 32)

Exomes 𝑓: 0.011 ( 110 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.67

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=0.008241266).

BP6

Variant 6-75105234-A-G is Benign according to our data. Variant chr6-75105234-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75105234-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00911 (1387/152262) while in subpopulation NFE AF= 0.01 (682/68024). AF 95% confidence interval is 0.0094. There are 12 homozygotes in gnomad4. There are 722 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6 linkuse as main transcript	c.8237T>C	p.Val2746Ala	missense_variant	54/66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13 linkuse as main transcript	c.8237T>C	p.Val2746Ala	missense_variant	54/66	1	NM_004370.6	ENSP00000325146	P4	Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.00912

AC:

1388

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.0429

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0347

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00961

AC:

2395

AN:

249184

Hom.:

AF XY:

0.00956

AC XY:

1293

AN XY:

135184

show subpopulations

Gnomad AFR exome

AF:

0.00213

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.0339

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00235

Gnomad FIN exome

AF:

0.0285

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.00778

GnomAD4 exome

AF:

0.0111

AC:

16155

AN:

1461504

Hom.:

110

Cov.:

AF XY:

0.0108

AC XY:

7850

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.00166

Gnomad4 ASJ exome

AF:

0.0318

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00252

Gnomad4 FIN exome

AF:

0.0262

Gnomad4 NFE exome

AF:

0.0116

Gnomad4 OTH exome

AF:

0.0111

GnomAD4 genome

AF:

0.00911

AC:

1387

AN:

152262

Hom.:

Cov.:

AF XY:

0.00970

AC XY:

722

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00226

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.0429

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.0347

Gnomad4 NFE

AF:

0.0100

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.0102

Hom.:

Bravo

AF:

0.00681

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00214

AC:

ESP6500EA

AF:

0.0126

AC:

104

ExAC

AF:

0.00924

AC:

1116

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00758

EpiControl

AF:

0.00895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	COL12A1: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0065

.;T;T;.;.;.

Eigen

Benign

0.052

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.75

T;T;T;T;T;T

MetaRNN

Benign

0.0082

T;T;T;T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

0.47

.;.;N;.;.;.

MutationTaster

Benign

0.59

N;N;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.14

N;.;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.82

T;.;T;T;T;T

Sift4G

Benign

0.95

T;T;T;T;T;T

Polyphen

0.87, 0.71

.;.;P;P;.;.

Vest4

0.37, 0.49, 0.41, 0.47, 0.37

MVP

0.80

MPC

0.85

ClinPred

0.034

GERP RS

5.6

Varity_R

0.11

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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