chr1-44828037-G-A

Position:

chr1-44828037-G-A

Variant summary

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

The NM_003738.5(PTCH2):c.1864C>T(p.His622Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0118 in 1,614,188 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H622N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0089 ( 6 hom., cov: 33)

Exomes 𝑓: 0.012 ( 120 hom. )

Consequence

PTCH2
NM_003738.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.05

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=0.0067539215).

BP6

Variant 1-44828037-G-A is Benign according to our data. Variant chr1-44828037-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 239555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-44828037-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 1355 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5 linkuse as main transcript	c.1864C>T	p.His622Tyr	missense_variant	14/22	ENST00000372192.4	NP_003729.3	Q9Y6C5-1
PTCH2	NM_001166292.2 linkuse as main transcript	c.1864C>T	p.His622Tyr	missense_variant	14/23		NP_001159764.1	Q9Y6C5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4 linkuse as main transcript	c.1864C>T	p.His622Tyr	missense_variant	14/22	1	NM_003738.5	ENSP00000361266.3		Q9Y6C5-1
PTCH2	ENST00000447098.6 linkuse as main transcript	c.1864C>T	p.His622Tyr	missense_variant	14/23	1		ENSP00000389703.2		Q9Y6C5-2

Frequencies

GnomAD3 genomes

AF:

0.00889

AC:

1354

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00207

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0134

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0147

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00947

AC:

2376

AN:

250818

Hom.:

AF XY:

0.00950

AC XY:

1288

AN XY:

135624

show subpopulations

Gnomad AFR exome

AF:

0.00221

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00519

Gnomad FIN exome

AF:

0.0125

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.00832

GnomAD4 exome

AF:

0.0121

AC:

17708

AN:

1461834

Hom.:

120

Cov.:

AF XY:

0.0119

AC XY:

8666

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.00226

Gnomad4 ASJ exome

AF:

0.00459

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00540

Gnomad4 FIN exome

AF:

0.0125

Gnomad4 NFE exome

AF:

0.0141

Gnomad4 OTH exome

AF:

0.00907

GnomAD4 genome

AF:

0.00889

AC:

1355

AN:

152354

Hom.:

Cov.:

AF XY:

0.00863

AC XY:

643

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0134

Gnomad4 NFE

AF:

0.0147

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.0124

Hom.:

Bravo

AF:

0.00757

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0138

AC:

119

ExAC

AF:

0.0101

AC:

1221

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0126

EpiControl

AF:

0.0102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2022	This variant is associated with the following publications: (PMID: 29230040) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PTCH2 p.His622Tyr variant was not identified in the Cosmic database but was identified in dbSNP (ID: rs11573586), ClinVar (reported by Invitae as benign for Basal cell nervus syndrome.), Clinvitae, MutDB (categorized as a polymorphism by SwissProt) and LOVD 3.0. The variant was identified in control databases in 2717 of 282218 chromosomes (26 homozygous) at a frequency of 0.009627 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 2003 of 128572 chromosomes (freq: 0.01558), European (Finnish) in 315 of 25086 chromosomes (freq: 0.01256), other in 62 of 7220 chromosomes (freq: 0.008587), South Asian in 159 of 30616 chromosomes (freq: 0.005193), Ashkenazi Jewish in 42 of 10368 chromosomes (freq: 0.004051), African in 56 of 24968 chromosomes (freq: 0.002243), Latino in 78 of 35434 chromosomes (freq: 0.002201) and East Asian in 2 of 19954 chromosomes (freq: 0.0001). The variant was identified in a patient with rhabdomyosarcoma with a maternally inherited PTCH1 mutation and the p.H622Y PTCH2 mutation inherited paternally (Taeubner_2017_29230040). This variant was also identified in two patients with basal cell carcinomas, however these patients also had PTCH1 mutations (Skvara_2011_21430703). The p.His622Tyr residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PTCH2: BS1, BS2 -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Basal cell carcinoma, susceptibility to, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Gorlin syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

PTCH2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

.;T

Eigen

Benign

-0.16

Eigen_PC

Benign

0.018

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

T;T

MetaRNN

Benign

0.0068

T;T

MetaSVM

Uncertain

-0.093

MutationAssessor

Benign

0.60

N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.23

Sift

Benign

0.036

D;D

Sift4G

Uncertain

0.053

T;D

Polyphen

0.0030

B;B

Vest4

0.25

MPC

0.20

ClinPred

0.010

GERP RS

4.3

Varity_R

0.15

gMVP

0.52

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

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