rs201988277

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting

The NM_004370.6(COL12A1):c.7853C>T(p.Thr2618Met) variant causes a missense change. The variant allele was found at a frequency of 0.000394 in 1,547,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2618T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1O:1

Conservation

PhyloP100: 6.22

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 Likely_benign. Variant got -2 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=0.0746977).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000405 (565/1395994) while in subpopulation NFE AF= 0.000456 (494/1083068). AF 95% confidence interval is 0.000423. There are 0 homozygotes in gnomad4_exome. There are 273 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6 linkuse as main transcript	c.7853C>T	p.Thr2618Met	missense_variant	51/66	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.7853C>T	p.Thr2618Met	missense_variant	51/66	1	NM_004370.6	ENSP00000325146.8		Q99715-1

Frequencies

GnomAD3 genomes

AF:

0.000297

AC:

AN:

151686

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000854

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000458

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000300

AC:

AN:

206788

Hom.:

AF XY:

0.000325

AC XY:

AN XY:

113724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000417

Gnomad FIN exome

AF:

0.000939

Gnomad NFE exome

AF:

0.000417

Gnomad OTH exome

AF:

0.000418

GnomAD4 exome

AF:

0.000405

AC:

565

AN:

1395994

Hom.:

Cov.:

AF XY:

0.000394

AC XY:

273

AN XY:

693284

show subpopulations

Gnomad4 AFR exome

AF:

0.000167

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000276

Gnomad4 SAS exome

AF:

0.0000135

Gnomad4 FIN exome

AF:

0.000855

Gnomad4 NFE exome

AF:

0.000456

Gnomad4 OTH exome

AF:

0.000313

GnomAD4 genome

AF:

0.000296

AC:

AN:

151802

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000854

Gnomad4 NFE

AF:

0.000458

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000425

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000493

AC:

ExAC

AF:

0.000273

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2024	Has been reported as likely pathogenic in a female with clinical features of Ehlers-Danlos syndrome (PMID: 36421793); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32214361, 36421793) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 22, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 06, 2021	- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 04-23-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

.;T;D;.;.;.;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.075

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

.;.;M;.;M;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-4.3

D;.;D;D;D;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0020

D;.;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D

Polyphen

1.0

.;.;D;D;.;.;.

Vest4

0.40, 0.51, 0.61, 0.64, 0.54

MVP

0.56

MPC

0.99

ClinPred

0.34

GERP RS

5.8

Varity_R

0.23

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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