Variant rs777389212 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_003738.5(PTCH2):c.3500C>T(p.Pro1167Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,948 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PTCH2
NM_003738.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.81

Variant links:

Genes affected

PTCH2 (HGNC:9586): (patched 2) This gene encodes a transmembrane receptor of the patched gene family. The encoded protein may function as a tumor suppressor in the hedgehog signaling pathway. Alterations in this gene have been associated with nevoid basal cell carcinoma syndrome, basal cell carcinoma, medulloblastoma, and susceptibility to congenital macrostomia. Alternatively spliced transcript variants have been described.[provided by RefSeq, Oct 2009]

PTCH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36344117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH2	NM_003738.5 linkuse as main transcript	c.3500C>T	p.Pro1167Leu	missense_variant	22/22	ENST00000372192.4
PTCH2	NM_001166292.2 linkuse as main transcript	c.3425+75C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH2	ENST00000372192.4 linkuse as main transcript	c.3500C>T	p.Pro1167Leu	missense_variant	22/22	1	NM_003738.5	P2	Q9Y6C5-1
PTCH2	ENST00000447098.6 linkuse as main transcript	c.3425+75C>T		intron_variant		1		A2	Q9Y6C5-2
PTCH2	ENST00000438067.5 linkuse as main transcript	c.186+75C>T		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251180

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135764

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Gorlin syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1167 of the PTCH2 protein (p.Pro1167Leu). This variant is present in population databases (rs777389212, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PTCH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 573292). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Uncertain

-0.070

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.86

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.36

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.013

Polyphen

0.89

Vest4

0.36

MutPred

0.30

Loss of glycosylation at P1167 (P = 0.0072);

MVP

0.95

MPC

0.71

ClinPred

0.58

GERP RS

4.6

Varity_R

0.20

gMVP

0.54

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