1-44822426-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003738.5(PTCH2):c.3601G>C(p.Ala1201Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.579

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07326341).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH2	NM_003738.5	c.3601G>C	p.Ala1201Pro	missense_variant	22/22	ENST00000372192.4
PTCH2	NM_001166292.2	c.3425+176G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH2	ENST00000372192.4	c.3601G>C	p.Ala1201Pro	missense_variant	22/22	1	NM_003738.5	P2
PTCH2	ENST00000447098.6	c.3425+176G>C		intron_variant		1		A2
PTCH2	ENST00000438067.5	c.186+176G>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461486 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

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

Jan 14, 2022

This variant has not been reported in the literature in individuals affected with PTCH2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1201 of the PTCH2 protein (p.Ala1201Pro). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. -

PTCH2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2023

The PTCH2 c.3601G>C variant is predicted to result in the amino acid substitution p.Ala1201Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	0.0064	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	12
Dann	Benign	0.97
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.25
Sift	Uncertain	0.023	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.13
MutPred		0.13		Gain of glycosylation at A1201 (P = 0.0276);
MVP		0.57
MPC		0.22
ClinPred		0.28	T
GERP RS		-3.3
Varity_R		0.14
gMVP		0.30

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

Other links and lift over

dbSNP: rs1454339215; hg19: chr1-45288098;