rs545773315

Positions:

• chr1-44822554-G-A
• chr1-44822554-G-C

Variant summary

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

The NM_003738.5(PTCH2):​c.3473C>T​(p.Thr1158Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.55

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=0.17372203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5	c.3473C>T	p.Thr1158Ile	missense_variant	22/22	ENST00000372192.4	NP_003729.3
PTCH2	NM_001166292.2	c.3425+48C>T		intron_variant			NP_001159764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4	c.3473C>T	p.Thr1158Ile	missense_variant	22/22	1	NM_003738.5	ENSP00000361266	P2
PTCH2	ENST00000447098.6	c.3425+48C>T		intron_variant		1		ENSP00000389703	A2
PTCH2	ENST00000438067.5	c.186+48C>T		intron_variant		3		ENSP00000413169

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1158 of the PTCH2 protein (p.Thr1158Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTCH2-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.16
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.13	T
Polyphen		0.18	B
Vest4		0.11
MutPred		0.26		Loss of sheet (P = 0.0011);
MVP		0.89
MPC		0.22
ClinPred		0.69	D
GERP RS		4.6
Varity_R		0.12
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-45288226;