rs35851686

Variant names:

• chr1-44829021-C-T
• rs35851686
• NM_003738.5:c.1425G>A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_003738.5(PTCH2):​c.1425G>A​(p.Ala475Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,578,544 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (2 hom.)
• Consequence: PTCH2 NM_003738.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.186

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 1-44829021-C-T is Benign according to our data. Variant chr1-44829021-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-44829021-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.186 with no splicing effect.
• BS2: High AC in GnomAd4 at 226 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH2	NM_003738.5	c.1425G>A	p.Ala475Ala	synonymous_variant	Exon 11 of 22	ENST00000372192.4	NP_003729.3
PTCH2	NM_001166292.2	c.1425G>A	p.Ala475Ala	synonymous_variant	Exon 11 of 23		NP_001159764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4	c.1425G>A	p.Ala475Ala	synonymous_variant	Exon 11 of 22	1	NM_003738.5	ENSP00000361266.3
PTCH2	ENST00000447098.6	c.1425G>A	p.Ala475Ala	synonymous_variant	Exon 11 of 23	1		ENSP00000389703.2

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00146 AC: 283 AN: 193458 Hom.: 1 AF XY: 0.00141 AC XY: 146 AN XY: 103832

Gnomad AFR exome AF: 0.0000871

Gnomad AMR exome AF: 0.000785

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000194

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00215 AC: 3060 AN: 1426286 Hom.: 2 Cov.: 32 AF XY: 0.00202 AC XY: 1430 AN XY: 706176

Gnomad4 AFR exome AF: 0.000429

Gnomad4 AMR exome AF: 0.000749

Gnomad4 ASJ exome AF: 0.00212

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000256

Gnomad4 FIN exome AF: 0.00102

Gnomad4 NFE exome AF: 0.00255

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74442

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00262

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00131

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Basal cell carcinoma, susceptibility to, 1 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gorlin syndrome Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PTCH2-related disorder Benign:1

Oct 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

not provided Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTCH2: BP4, BP7 -

Basal cell nevus syndrome 1 Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.3
DANN	Benign	0.61

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

Other links and lift over

dbSNP: rs35851686; hg19: chr1-45294693;