rs240736

Positions:

chr6-75138465-A-G

Variant summary

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

The NM_004370.6(COL12A1):c.5213T>C(p.Ile1738Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,613,334 control chromosomes in the GnomAD database, including 64,381 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1738M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.29 ( 6440 hom., cov: 32)

Exomes 𝑓: 0.28 ( 57941 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.403

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=0.0029047132).

BP6

Variant 6-75138465-A-G is Benign according to our data. Variant chr6-75138465-A-G is described in ClinVar as [Benign]. Clinvar id is 259336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75138465-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6 linkuse as main transcript	c.5213T>C	p.Ile1738Thr	missense_variant	29/66	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.5213T>C	p.Ile1738Thr	missense_variant	29/66	1	NM_004370.6	ENSP00000325146	P4	Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.290

AC:

44099

AN:

151970

Hom.:

6440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.330

Gnomad AMI

AF:

0.303

Gnomad AMR

AF:

0.295

Gnomad ASJ

AF:

0.297

Gnomad EAS

AF:

0.144

Gnomad SAS

AF:

0.232

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.288

Gnomad OTH

AF:

0.297

GnomAD3 exomes

AF:

0.264

AC:

65633

AN:

248634

Hom.:

9011

AF XY:

0.263

AC XY:

35417

AN XY:

134886

show subpopulations

Gnomad AFR exome

AF:

0.330

Gnomad AMR exome

AF:

0.277

Gnomad ASJ exome

AF:

0.278

Gnomad EAS exome

AF:

0.148

Gnomad SAS exome

AF:

0.227

Gnomad FIN exome

AF:

0.229

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.272

GnomAD4 exome

AF:

0.279

AC:

407739

AN:

1461246

Hom.:

57941

Cov.:

AF XY:

0.277

AC XY:

201551

AN XY:

726876

show subpopulations

Gnomad4 AFR exome

AF:

0.335

Gnomad4 AMR exome

AF:

0.282

Gnomad4 ASJ exome

AF:

0.281

Gnomad4 EAS exome

AF:

0.142

Gnomad4 SAS exome

AF:

0.231

Gnomad4 FIN exome

AF:

0.232

Gnomad4 NFE exome

AF:

0.288

Gnomad4 OTH exome

AF:

0.272

GnomAD4 genome

AF:

0.290

AC:

44110

AN:

152088

Hom.:

6440

Cov.:

AF XY:

0.286

AC XY:

21231

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.330

Gnomad4 AMR

AF:

0.295

Gnomad4 ASJ

AF:

0.297

Gnomad4 EAS

AF:

0.145

Gnomad4 SAS

AF:

0.231

Gnomad4 FIN

AF:

0.231

Gnomad4 NFE

AF:

0.288

Gnomad4 OTH

AF:

0.294

Alfa

AF:

0.284

Hom.:

15656

Bravo

AF:

0.296

TwinsUK

AF:

0.305

AC:

1132

ALSPAC

AF:

0.267

AC:

1029

ESP6500AA

AF:

0.308

AC:

1179

ESP6500EA

AF:

0.285

AC:

2364

ExAC

AF:

0.264

AC:

31933

Asia WGS

AF:

0.197

AC:

690

AN:

3476

EpiCase

AF:

0.287

EpiControl

AF:

0.291

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -

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 05, 2018

- -

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

0.053

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.91

DANN

Benign

0.54

DEOGEN2

Benign

0.0026

T;T;.;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.83

T;T;T;T;T

MetaRNN

Benign

0.0029

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.20

.;N;.;N;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.43

.;N;N;N;N

REVEL

Benign

0.29

Sift

Benign

0.57

.;T;T;T;T

Sift4G

Benign

0.64

T;T;T;T;T

Polyphen

0.0

.;B;B;.;.

Vest4

0.015

MPC

0.15

ClinPred

0.0080

GERP RS

-12

Varity_R

0.028

gMVP

0.37

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