rs202184038

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003738.5(PTCH2):c.3269C>T(p.Ala1090Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1090A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

PTCH2
NM_003738.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.37

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05075839).

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH2	NM_003738.5 link	c.3269C>T	p.Ala1090Val	missense_variant	Exon 21 of 22	ENST00000372192.4	NP_003729.3	Q9Y6C5-1
PTCH2	NM_001166292.2 link	c.3269C>T	p.Ala1090Val	missense_variant	Exon 21 of 23		NP_001159764.1	Q9Y6C5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PTCH2	ENST00000372192.4 link	c.3269C>T	p.Ala1090Val	missense_variant	Exon 21 of 22	1	NM_003738.5	ENSP00000361266.3	Q9Y6C5-1
PTCH2	ENST00000447098.6 link	c.3269C>T	p.Ala1090Val	missense_variant	Exon 21 of 23	1		ENSP00000389703.2	Q9Y6C5-2
PTCH2	ENST00000438067.5 link	c.29C>T	p.Ala10Val	missense_variant	Exon 2 of 5	3		ENSP00000413169.1	H0Y7J2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000309

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000155

AC:

AN:

250814

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000217

AC:

317

AN:

1461824

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000271

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000151

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000309

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.000313

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Basal cell carcinoma, susceptibility to, 1

Uncertain:1

Jun 23, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gorlin syndrome

Uncertain:1

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1090 of the PTCH2 protein (p.Ala1090Val). This variant is present in population databases (rs202184038, gnomAD 0.03%). 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: 453937). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PTCH2 protein function with a negative predictive value of 80%. 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. -

Basal cell nevus syndrome 1

Uncertain:1

May 15, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTCH2 c.3269C>T (p.Ala1090Val) missense change has a maximum subpopulation frequency of 0.026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. This variant has not been reported in individuals with nevoid basal cell carcinoma syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.14

.;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.051

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.90

L;L

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.23

N;N

REVEL

Benign

0.26

Sift

Benign

0.50

T;T

Sift4G

Benign

0.54

T;T

Polyphen

0.0010

B;B

Vest4

0.26

MVP

0.65

MPC

0.17

ClinPred

0.015

GERP RS

2.7

Varity_R

0.043

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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