1-44827254-C-G

Position:

chr1-44827254-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003738.5(PTCH2):c.2427G>C(p.Ser809Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,614,134 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S809S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 19 hom., cov: 33)

Exomes 𝑓: 0.013 ( 166 hom. )

Consequence

PTCH2
NM_003738.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.17

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 1-44827254-C-G is Benign according to our data. Variant chr1-44827254-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 239557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-44827254-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.17 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0112 (1705/152314) while in subpopulation NFE AF= 0.0185 (1257/68008). AF 95% confidence interval is 0.0176. There are 19 homozygotes in gnomad4. There are 818 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1705 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5 link	c.2427G>C	p.Ser809Ser	synonymous_variant	16/22	ENST00000372192.4	NP_003729.3	Q9Y6C5-1
PTCH2	NM_001166292.2 link	c.2427G>C	p.Ser809Ser	synonymous_variant	16/23		NP_001159764.1	Q9Y6C5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4 link	c.2427G>C	p.Ser809Ser	synonymous_variant	16/22	1	NM_003738.5	ENSP00000361266.3		Q9Y6C5-1
PTCH2	ENST00000447098.6 link	c.2427G>C	p.Ser809Ser	synonymous_variant	16/23	1		ENSP00000389703.2		Q9Y6C5-2

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1705

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0191

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.0119

AC:

2986

AN:

251368

Hom.:

AF XY:

0.0120

AC XY:

1633

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.00804

Gnomad ASJ exome

AF:

0.0125

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00199

Gnomad FIN exome

AF:

0.0182

Gnomad NFE exome

AF:

0.0174

Gnomad OTH exome

AF:

0.0184

GnomAD4 exome

AF:

0.0130

AC:

19044

AN:

1461820

Hom.:

166

Cov.:

AF XY:

0.0129

AC XY:

9396

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.00865

Gnomad4 ASJ exome

AF:

0.0132

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00233

Gnomad4 FIN exome

AF:

0.0188

Gnomad4 NFE exome

AF:

0.0146

Gnomad4 OTH exome

AF:

0.0114

GnomAD4 genome

AF:

0.0112

AC:

1705

AN:

152314

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

818

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00712

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00310

Gnomad4 FIN

AF:

0.0191

Gnomad4 NFE

AF:

0.0185

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.0130

Hom.:

Bravo

AF:

0.00977

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0170

EpiControl

AF:

0.0176

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PTCH2: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2021	- -

not specified

Benign:2

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

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

Aug 28, 2019

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

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.16

DANN

Benign

0.70

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