1-44831758-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_003738.5(PTCH2):​c.565C>G​(p.Leu189Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000492 in 1,586,836 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L189I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

PTCH2
NM_003738.5 missense

Scores

5
11
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.51
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.3665654).
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTCH2NM_003738.5 linkc.565C>G p.Leu189Val missense_variant Exon 5 of 22 ENST00000372192.4 NP_003729.3 Q9Y6C5-1
PTCH2NM_001166292.2 linkc.565C>G p.Leu189Val missense_variant Exon 5 of 23 NP_001159764.1 Q9Y6C5-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTCH2ENST00000372192.4 linkc.565C>G p.Leu189Val missense_variant Exon 5 of 22 1 NM_003738.5 ENSP00000361266.3 Q9Y6C5-1
PTCH2ENST00000447098.6 linkc.565C>G p.Leu189Val missense_variant Exon 5 of 23 1 ENSP00000389703.2 Q9Y6C5-2

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152136
Hom.:
0
Cov.:
32
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:
0.000193
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000726
AC:
15
AN:
206568
Hom.:
0
AF XY:
0.0000718
AC XY:
8
AN XY:
111394
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000102
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000134
Gnomad SAS exome
AF:
0.000185
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000444
Gnomad OTH exome
AF:
0.000188
GnomAD4 exome
AF:
0.0000495
AC:
71
AN:
1434582
Hom.:
0
Cov.:
32
AF XY:
0.0000478
AC XY:
34
AN XY:
711478
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000752
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000168
Gnomad4 FIN exome
AF:
0.0000193
Gnomad4 NFE exome
AF:
0.0000310
Gnomad4 OTH exome
AF:
0.000202
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000378
ExAC
AF:
0.0000744
AC:
9
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma;C2751544:Basal cell carcinoma, susceptibility to, 1 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

PTCH2-related disorder Uncertain:1
Mar 07, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PTCH2 c.565C>G variant is predicted to result in the amino acid substitution p.Leu189Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.018% of alleles in individuals of South Asian descent in gnomAD. This variant is classified as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/524558/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Gorlin syndrome Uncertain:1
May 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 189 of the PTCH2 protein (p.Leu189Val). This variant is present in population databases (rs747885797, gnomAD 0.02%). 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: 524558). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTCH2 protein function. 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. -

not provided Uncertain:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Medulloblastoma;C2751544:Basal cell carcinoma, susceptibility to, 1 Uncertain:1
Feb 15, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.20
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.66
.;D
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.37
T;T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.3
M;M
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-2.8
D;D
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.61
MutPred
0.47
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
0.98
MPC
0.71
ClinPred
0.32
T
GERP RS
4.5
Varity_R
0.62
gMVP
0.83

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.

Other links and lift over

dbSNP: rs747885797; hg19: chr1-45297430; COSMIC: COSV64713548; API