Variant rs763413121 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003738.5(PTCH2):c.3505delC(p.Leu1169CysfsTer85) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,610,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

PTCH2
NM_003738.5 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.983

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 Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH2	NM_003738.5 link	c.3505delC	p.Leu1169CysfsTer85	frameshift_variant	Exon 22 of 22	ENST00000372192.4	NP_003729.3	Q9Y6C5-1
PTCH2	NM_001166292.2 link	c.3425+80delC		intron_variant	Intron 22 of 22		NP_001159764.1	Q9Y6C5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PTCH2	ENST00000372192.4 link	c.3505delC	p.Leu1169CysfsTer85	frameshift_variant	Exon 22 of 22	1	NM_003738.5	ENSP00000361266.3	Q9Y6C5-1
PTCH2	ENST00000447098.6 link	c.3425+80delC		intron_variant	Intron 22 of 22	1		ENSP00000389703.2	Q9Y6C5-2
PTCH2	ENST00000438067.5 link	c.185+80delC		intron_variant	Intron 3 of 4	3		ENSP00000413169.1	H0Y7J2

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151688

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000798

AC:

AN:

250492

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000400

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1459182

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

725880

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000345

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000631

Gnomad4 OTH exome

AF:

0.0000996

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151806

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000302

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Gorlin syndrome

Uncertain:1

Sep 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. ClinVar contains an entry for this variant (Variation ID: 1048946). This variant has not been reported in the literature in individuals affected with PTCH2-related conditions. This variant is present in population databases (rs766993839, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This sequence change results in a frameshift in the PTCH2 gene (p.Leu1169Cysfs*85). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the PTCH2 protein and extend the protein by 49 additional amino acid residues. -

not provided

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTCH2 p.Leu1169Cysfs*85 variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs766993839), Cosmic and in control databases in 22 of 281788 chromosomes at a frequency of 0.000078 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 4 of 10294 chromosomes (freq: 0.000389), East Asian in 6 of 19940 chromosomes (freq: 0.000301), Other in 1 of 7202 chromosomes (freq: 0.000139), Latino in 4 of 35406 chromosomes (freq: 0.000113), South Asian in 3 of 30584 chromosomes (freq: 0.000098) and European (non-Finnish) in 4 of 128460 chromosomes (freq: 0.000031), while the variant was not observed in the African or European (Finnish) populations. The c.3505del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1169 and leads to a premature stop codon 85 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. It is currently unclear if loss of function variants of the PTCH2 gene are a mechanism of disease. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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