rs11573598

Positions:

chr1-44822664-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003738.5(PTCH2):c.3363A>G(p.Ile1121Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

PTCH2
NM_003738.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.883

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043581724).

BP6

Variant 1-44822664-T-C is Benign according to our data. Variant chr1-44822664-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 415451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5 linkuse as main transcript	c.3363A>G	p.Ile1121Met	missense_variant	22/22	ENST00000372192.4	NP_003729.3	Q9Y6C5-1
PTCH2	NM_001166292.2 linkuse as main transcript	c.3363A>G	p.Ile1121Met	missense_variant	22/23		NP_001159764.1	Q9Y6C5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PTCH2	ENST00000372192.4 linkuse as main transcript	c.3363A>G	p.Ile1121Met	missense_variant	22/22	1	NM_003738.5	ENSP00000361266.3	Q9Y6C5-1
PTCH2	ENST00000447098.6 linkuse as main transcript	c.3363A>G	p.Ile1121Met	missense_variant	22/23	1		ENSP00000389703.2	Q9Y6C5-2
PTCH2	ENST00000438067.5 linkuse as main transcript	c.123A>G	p.Ile41Met	missense_variant	3/5	3		ENSP00000413169.1	H0Y7J2

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00512

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000358

AC:

AN:

251210

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.00468

Gnomad AMR exome

AF:

0.000347

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:

0.00000881

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000180

AC:

263

AN:

1461624

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00615

Gnomad4 AMR exome

AF:

0.000447

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:

0.0000108

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.00144

AC:

219

AN:

152176

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00511

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000602

Hom.:

Bravo

AF:

0.00163

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000461

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PTCH2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Gorlin syndrome;C0025149:Medulloblastoma;C2751544:Basal cell carcinoma, susceptibility to, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 11, 2021

- -

Gorlin syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.18

.;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.0044

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.80

N;N

REVEL

Benign

0.24

Sift

Uncertain

0.027

D;D

Sift4G

Uncertain

0.044

D;T

Polyphen

0.0

B;B

Vest4

0.10

MVP

0.84

MPC

0.17

ClinPred

0.0018

GERP RS

-2.8

Varity_R

0.11

gMVP

0.32

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over