1-44827437-C-T

Variant summary

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

The NM_003738.5(PTCH2):​c.2336G>A​(p.Arg779His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,842 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. R779C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PTCH2
NM_003738.5 missense

Scores

1
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.98
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 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTCH2NM_003738.5 linkc.2336G>A p.Arg779His missense_variant 15/22 ENST00000372192.4 NP_003729.3 Q9Y6C5-1
PTCH2NM_001166292.2 linkc.2336G>A p.Arg779His missense_variant 15/23 NP_001159764.1 Q9Y6C5-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTCH2ENST00000372192.4 linkc.2336G>A p.Arg779His missense_variant 15/221 NM_003738.5 ENSP00000361266.3 Q9Y6C5-1
PTCH2ENST00000447098.6 linkc.2336G>A p.Arg779His missense_variant 15/231 ENSP00000389703.2 Q9Y6C5-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250682
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135662
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1460842
Hom.:
0
Cov.:
37
AF XY:
0.00000275
AC XY:
2
AN XY:
726756
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

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), LabcorpSep 11, 2020Algorithms 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PTCH2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 779 of the PTCH2 protein (p.Arg779His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. 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
0.089
BayesDel_addAF
Benign
-0.040
T
BayesDel_noAF
Benign
-0.20
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.19
.;T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Benign
0.69
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Uncertain
0.57
D;D
MetaSVM
Uncertain
-0.0053
T
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-1.2
N;N
REVEL
Uncertain
0.48
Sift
Uncertain
0.028
D;D
Sift4G
Benign
0.076
T;T
Polyphen
0.98
D;D
Vest4
0.56
MutPred
0.55
Loss of MoRF binding (P = 0.0135);Loss of MoRF binding (P = 0.0135);
MVP
0.91
MPC
0.54
ClinPred
0.98
D
GERP RS
4.8
Varity_R
0.078
gMVP
0.52

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: rs45493198; hg19: chr1-45293109; API