chr1-44823079-G-A

Position:

chr1-44823079-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003738.5(PTCH2):c.3347C>T(p.Pro1116Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P1116P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

PTCH2
NM_003738.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.35

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 -4 ACMG points.

BS2

High AC in GnomAdExome4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5 linkuse as main transcript	c.3347C>T	p.Pro1116Leu	missense_variant	21/22	ENST00000372192.4	NP_003729.3	Q9Y6C5-1
PTCH2	NM_001166292.2 linkuse as main transcript	c.3347C>T	p.Pro1116Leu	missense_variant	21/23		NP_001159764.1	Q9Y6C5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PTCH2	ENST00000372192.4 linkuse as main transcript	c.3347C>T	p.Pro1116Leu	missense_variant	21/22	1	NM_003738.5	ENSP00000361266.3	Q9Y6C5-1
PTCH2	ENST00000447098.6 linkuse as main transcript	c.3347C>T	p.Pro1116Leu	missense_variant	21/23	1		ENSP00000389703.2	Q9Y6C5-2
PTCH2	ENST00000438067.5 linkuse as main transcript	c.107C>T	p.Pro36Leu	missense_variant	2/5	3		ENSP00000413169.1	H0Y7J2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152136

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000808

AC:

AN:

247660

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133986

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1461068

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726760

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:

0.0000531

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gorlin syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics, Children's Hospital New Orleans	Jul 29, 2019	We report a male patient with a novel PTCH2 variant of uncertain significance inherited from the father. The proband displays several minor diagnostic findings observed in individuals with Gorlin syndrome, supporting the pathogenic role of this gene. Phenotypic features in the proband include macrocephaly, a wide face, prominent forehead, hypertelorism and telecanthus, large eyes, cleft lip and palate, thin vertical palmar creases, penoscrotal inversion, and a hyperpigmented spot on his penis. The father displays macrocephaly, several nevi on his back and shoulders, and a single palmar pit on his left hand, raising suspicion for Gorlin syndrome. PTCH2 encodes a transmembrane receptor of the patched gene family. It has been suggested that PTCH2 is a functional Sonic hedgehog receptor, and has tumor-suppressor function (Fan et al., 2008; MIM 603673; Zhulyn et al., 2015). A heterozygous missense variant in PTCH2 has been reported in one family in association with nevoid basal cell carcinoma syndrome (NBCCS) (Fan et al., 2008). Another patient with NBCCS was found to have a frameshift variant resulting in truncation of the PTCH2 protein and haploinsufficiency (Fujii et al., 2013). NBCCS is an autosomal dominant condition characterized by lamellar calcification of the falx, jaw keratocyst, palmar/plantar pits, and multiple basal cell carcinomas in addition to skeletal anomalies, macrocephaly, oral clefting, ovarian/cardiac fibroma, lymphomesenteric cysts and ocular abnormalities; however, intra- and interfamilial variability has been observed (Evans and Farndon, 2013; Bree et al., 2011). This semi-conservative amino acid substitution has not been reported in the literature as either a benign or pathogenic variant. Two entries exist within a whole exome sequencing healthy population reference database for this missense variant, once in an individual of East Asian decent and once in an individual of European non-Finnish descent, suggesting an allele frequency of 0.000008076 (gnomAD), raising the possibility of a rare benign variant. Other variants at this codon have been reported as well in healthy reference populations, again raising concerns that observed variant is rare and benign. While Gorlin syndrome displays complete penetrance when attributed to PTCH1 variants, several reported pathogenic PTCH2 variants have been identified in individuals with features of NBCCs as well as apparently healthy reference populations, suggesting incomplete penetrance in PTCH2-related disease (Fujii et al. 2013; Fan et al., 2008). A recent case report by Altaraihi et al. describes a homozygous mother and heterozygous daughter with a frameshift mutation in PTCH2. Although both patients display significant pathology, neither exhibit features characteristic of NBCCS, further challenging the pathogenicity of this gene in the context of Gorlin syndrome (Altaraihi et al. 2019). Available in silico analysis produces inconsistent, contradictory predictions regarding impact of this amino acid substitution on PTCH2 protein structure and function (Polyphen 2: benign, score 0.319; SIFT: Damaging; MutTaster: disease causing, score 0.999). Additional in silico modeling suggests that this variant may result in altered splicing or exon skipping (HSP3.1; Ex-Skip). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 24, 2023	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTCH2 protein function. ClinVar contains an entry for this variant (Variation ID: 453938). This missense change has been observed in individual(s) with clinical features of PTCH2-related conditions (PMID: 31945512). This variant is present in population databases (rs539161089, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1116 of the PTCH2 protein (p.Pro1116Leu). -

Gorlin syndrome;C0025149:Medulloblastoma;C2751544:Basal cell carcinoma, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

PTCH2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2024

The PTCH2 c.3347C>T variant is predicted to result in the amino acid substitution p.Pro1116Leu. This variant was reported in the heterozygous state in three family members with minor diagnostic features of a Gorlin syndrome-like phenotype (nevoid basal-cell carcinoma syndrome); however all three family members do not meet clinical criteria for Gorlin syndrome (Casano et al. 2020. PubMed ID: 31945512). This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD and is classified as a variant of uncertain significance in gnomAD (https://www.ncbi.nlm.nih.gov/clinvar/variation/453938/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

.;D

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Pathogenic

0.42

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.2

M;M

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-8.4

D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.61

P;P

Vest4

0.61

MutPred

0.59

Loss of glycosylation at P1116 (P = 0.0175);Loss of glycosylation at P1116 (P = 0.0175);

MVP

0.94

MPC

0.71

ClinPred

0.99

GERP RS

4.3

Varity_R

0.69

gMVP

0.81

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