1-44830923-G-C

Variant names:

• chr1-44830923-G-C
• rs58079936
• NM_003738.5:c.738C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003738.5(PTCH2):​c.738C>G​(p.Ala246Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,447,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A246A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PTCH2 NM_003738.5 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.76
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003738.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	NM_003738.5	MANE Select	c.738C>G	p.Ala246Ala	synonymous	Exon 6 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.738C>G	p.Ala246Ala	synonymous	Exon 6 of 23	NP_001159764.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	ENST00000372192.4	TSL:1 MANE Select	c.738C>G	p.Ala246Ala	synonymous	Exon 6 of 22	ENSP00000361266.3
	PTCH2	ENST00000447098.7	TSL:1	c.738C>G	p.Ala246Ala	synonymous	Exon 6 of 23	ENSP00000389703.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248434 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

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: 0.00000276 AC: 4 AN: 1447390 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717404

African (AFR) AF: 0.00 AC: 0 AN: 33206

American (AMR) AF: 0.0000226 AC: 1 AN: 44306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25818

East Asian (EAS) AF: 0.00 AC: 0 AN: 39270

South Asian (SAS) AF: 0.00 AC: 0 AN: 85630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5388

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1100964

Other (OTH) AF: 0.00 AC: 0 AN: 59606

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000451 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

PTCH2-related disorder Uncertain:1

Sep 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTCH2 c.738C>G variant is not predicted to result in an amino acid change (p.=). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1403063/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Gorlin syndrome Uncertain:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 246 of the PTCH2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PTCH2 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PTCH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1403063). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.79
PhyloP100		2.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 1

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

Other links and lift over

dbSNP: rs58079936; hg19: chr1-45296595;