1-44822443-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003738.5(PTCH2):c.3584C>T(p.Ser1195Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,774 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1195T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.090613395).
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH2	NM_003738.5	c.3584C>T	p.Ser1195Phe	missense_variant	22/22	ENST00000372192.4
PTCH2	NM_001166292.2	c.3425+159C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH2	ENST00000372192.4	c.3584C>T	p.Ser1195Phe	missense_variant	22/22	1	NM_003738.5	P2
PTCH2	ENST00000447098.6	c.3425+159C>T		intron_variant		1		A2
PTCH2	ENST00000438067.5	c.186+159C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250732 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135616

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000867

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461614 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727064

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74332

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000642

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2023

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1195 of the PTCH2 protein (p.Ser1195Phe). This variant is present in population databases (rs145536878, gnomAD 0.009%). 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: 2431791). 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. -

Breast carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Sep 16, 2022

ACMG classification criteria: PM2 supporting, BP4 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.091	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.027	D
Polyphen		0.14	B
Vest4		0.19
MVP		0.87
MPC		0.28
ClinPred		0.094	T
GERP RS		3.9
Varity_R		0.076
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs145536878; hg19: chr1-45288115;