rs111283762
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The ENST00000372192.4(PTCH2):c.446T>A(p.Leu149His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
PTCH2
ENST00000372192.4 missense
ENST00000372192.4 missense
Scores
12
4
3
Clinical Significance
Conservation
PhyloP100: 8.76
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.911
BS2
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTCH2 | NM_003738.5 | c.446T>A | p.Leu149His | missense_variant | 3/22 | ENST00000372192.4 | NP_003729.3 | |
PTCH2 | NM_001166292.2 | c.446T>A | p.Leu149His | missense_variant | 3/23 | NP_001159764.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PTCH2 | ENST00000372192.4 | c.446T>A | p.Leu149His | missense_variant | 3/22 | 1 | NM_003738.5 | ENSP00000361266 | P2 | |
PTCH2 | ENST00000447098.6 | c.446T>A | p.Leu149His | missense_variant | 3/23 | 1 | ENSP00000389703 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 151992Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251490Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135920
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727246
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74372
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Gorlin syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 01, 2023 | 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 not expected to disrupt PTCH2 protein function. ClinVar contains an entry for this variant (Variation ID: 453941). This variant has not been reported in the literature in individuals affected with PTCH2-related conditions. This variant is present in population databases (rs111283762, gnomAD 0.008%). This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 149 of the PTCH2 protein (p.Leu149His). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Nov 21, 2023 | The PTCH2 c.446T>A (p.Leu149His) missense change has a maximum subpopulation frequency of 0.0080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
MVP
MPC
0.78
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at