NM_003738.5:c.3154G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003738.5(PTCH2):​c.3154G>A​(p.Ala1052Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

PTCH2
NM_003738.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.58

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • nevoid basal cell carcinoma syndrome
    Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
  • commissural facial cleft
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12898272).
BS2
High AC in GnomAd4 at 11 AD,Unknown gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTCH2NM_003738.5 linkc.3154G>A p.Ala1052Thr missense_variant Exon 20 of 22 ENST00000372192.4 NP_003729.3 Q9Y6C5-1
PTCH2NM_001166292.2 linkc.3154G>A p.Ala1052Thr missense_variant Exon 20 of 23 NP_001159764.1 Q9Y6C5-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTCH2ENST00000372192.4 linkc.3154G>A p.Ala1052Thr missense_variant Exon 20 of 22 1 NM_003738.5 ENSP00000361266.3 Q9Y6C5-1
PTCH2ENST00000447098.7 linkc.3154G>A p.Ala1052Thr missense_variant Exon 20 of 23 1 ENSP00000389703.2 Q9Y6C5-2
PTCH2ENST00000438067.5 linkc.-87G>A upstream_gene_variant 3 ENSP00000413169.1 H0Y7J2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000358
AC:
9
AN:
251278
AF XY:
0.0000368
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000465
AC:
68
AN:
1461874
Hom.:
0
Cov.:
33
AF XY:
0.0000481
AC XY:
35
AN XY:
727236
show subpopulations
African (AFR)
AF:
0.000119
AC:
4
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.000153
AC:
4
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000185
AC:
16
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000342
AC:
38
AN:
1112012
Other (OTH)
AF:
0.0000993
AC:
6
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
6
12
17
23
29
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152226
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74376
show subpopulations
African (AFR)
AF:
0.000241
AC:
10
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 21, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3154G>A (p.A1052T) alteration is located in exon 20 (coding exon 20) of the PTCH2 gene. This alteration results from a G to A substitution at nucleotide position 3154, causing the alanine (A) at amino acid position 1052 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Gorlin syndrome Uncertain:1
Sep 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1052 of the PTCH2 protein (p.Ala1052Thr). This variant is present in population databases (rs139590197, 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: 453935). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PTCH2 protein function with a negative predictive value of 80%. 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
0.082
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
21
DANN
Benign
0.61
DEOGEN2
Benign
0.19
.;T
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.068
D
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
0.49
N;N
PhyloP100
3.6
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.11
N;N
REVEL
Benign
0.22
Sift
Benign
0.59
T;T
Sift4G
Benign
0.51
T;T
Polyphen
0.020
B;B
Vest4
0.47
MVP
0.73
MPC
0.17
ClinPred
0.028
T
GERP RS
3.3
PromoterAI
-0.0068
Neutral
Varity_R
0.097
gMVP
0.44
Mutation Taster
=81/19
polymorphism

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

Other links and lift over

dbSNP: rs139590197; hg19: chr1-45289018; API