rs369481564

Variant summary

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

The ENST00000372192.4(PTCH2):​c.1663C>T​(p.Arg555Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R555Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PTCH2
ENST00000372192.4 missense

Scores

3
12
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83
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 -4 ACMG points.

BS2
High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTCH2NM_003738.5 linkuse as main transcriptc.1663C>T p.Arg555Trp missense_variant 13/22 ENST00000372192.4 NP_003729.3
PTCH2NM_001166292.2 linkuse as main transcriptc.1663C>T p.Arg555Trp missense_variant 13/23 NP_001159764.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTCH2ENST00000372192.4 linkuse as main transcriptc.1663C>T p.Arg555Trp missense_variant 13/221 NM_003738.5 ENSP00000361266 P2Q9Y6C5-1
PTCH2ENST00000447098.6 linkuse as main transcriptc.1663C>T p.Arg555Trp missense_variant 13/231 ENSP00000389703 A2Q9Y6C5-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000319
AC:
8
AN:
250664
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135584
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461762
Hom.:
0
Cov.:
37
AF XY:
0.0000124
AC XY:
9
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 testingLabcorp Genetics (formerly Invitae), LabcorpJun 24, 2021This variant has not been reported in the literature in individuals with PTCH2-related disease. This variant is present in population databases (rs369481564, ExAC 0.01%). This sequence change replaces arginine with tryptophan at codon 555 of the PTCH2 protein (p.Arg555Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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
0.079
BayesDel_addAF
Benign
-0.053
T
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.93
.;D
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Uncertain
0.51
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.1
M;M
MutationTaster
Benign
0.93
D;D
PrimateAI
Benign
0.21
T
PROVEAN
Uncertain
-3.3
D;D
REVEL
Uncertain
0.58
Sift
Uncertain
0.0070
D;D
Sift4G
Uncertain
0.030
D;D
Polyphen
0.92
P;P
Vest4
0.43
MVP
0.96
MPC
0.52
ClinPred
0.66
D
GERP RS
3.0
Varity_R
0.19
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: rs369481564; hg19: chr1-45294014; COSMIC: COSV64710237; API