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GeneBe

1-44822498-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003738.5(PTCH2):c.3529G>T(p.Ala1177Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PTCH2
NM_003738.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0950
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.087685555).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTCH2NM_003738.5 linkuse as main transcriptc.3529G>T p.Ala1177Ser missense_variant 22/22 ENST00000372192.4
PTCH2NM_001166292.2 linkuse as main transcriptc.3425+104G>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTCH2ENST00000372192.4 linkuse as main transcriptc.3529G>T p.Ala1177Ser missense_variant 22/221 NM_003738.5 P2Q9Y6C5-1
PTCH2ENST00000447098.6 linkuse as main transcriptc.3425+104G>T intron_variant 1 A2Q9Y6C5-2
PTCH2ENST00000438067.5 linkuse as main transcriptc.186+104G>T intron_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250872
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135644
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461694
Hom.:
0
Cov.:
32
AF XY:
0.0000179
AC XY:
13
AN XY:
727136
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:
0.0000225
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 submitterclinical testingInvitaeDec 28, 2023This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1177 of the PTCH2 protein (p.Ala1177Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with PTCH2-related conditions. 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 tolerated. 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
0.080
BayesDel_addAF
Benign
-0.037
T
BayesDel_noAF
Benign
-0.28
Cadd
Benign
17
Dann
Uncertain
0.99
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.73
Eigen_PC
Benign
-0.64
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.76
T
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.088
T
MetaSVM
Benign
-0.55
T
MutationAssessor
Benign
0.55
N
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
0.47
N
REVEL
Benign
0.23
Sift
Uncertain
0.026
D
Sift4G
Benign
0.22
T
Polyphen
0.041
B
Vest4
0.081
MutPred
0.13
Gain of glycosylation at A1177 (P = 0.001);
MVP
0.77
MPC
0.16
ClinPred
0.088
T
GERP RS
2.7
Varity_R
0.074
gMVP
0.41

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: rs1416107461; hg19: chr1-45288170; API