1-44822436-TC-T

Variant names:

• chr1-44822436-TC-T
• rs773730257
• NM_003738.5:c.3590delG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_003738.5(PTCH2):​c.3590delG​(p.Gly1197AspfsTer57) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PTCH2 NM_003738.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.89
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• nevoid basal cell carcinoma syndrome

  Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• commissural facial cleft

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00609 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High AC in GnomAdExome4 at 27 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH2	NM_003738.5	c.3590delG	p.Gly1197AspfsTer57	frameshift_variant	Exon 22 of 22	ENST00000372192.4	NP_003729.3
PTCH2	NM_001166292.2	c.3425+165delG		intron_variant	Intron 22 of 22		NP_001159764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4	c.3590delG	p.Gly1197AspfsTer57	frameshift_variant	Exon 22 of 22	1	NM_003738.5	ENSP00000361266.3
PTCH2	ENST00000447098.7	c.3425+165delG		intron_variant	Intron 22 of 22	1		ENSP00000389703.2
PTCH2	ENST00000438067.5	c.185+165delG		intron_variant	Intron 3 of 4	3		ENSP00000413169.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250650 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461580 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727032

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Uncertain:1

May 07, 2022

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with PTCH2-related conditions. This variant is present in population databases (rs773730257, gnomAD 0.03%). This sequence change results in a frameshift in the PTCH2 gene (p.Gly1197Aspfs*57). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the PTCH2 protein and extend the protein by 49 additional amino acid residues. -

not provided Uncertain:1

Dec 19, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=27/173	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773730257; hg19: chr1-45288108;