rs11573587

chr1-44827646-G-Achr1-44827646-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003738.5(PTCH2):c.2127C>T(p.Asp709=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,613,342 control chromosomes in the GnomAD database, including 335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (21 hom., cov: 33)
  • Exomes 𝑓: 0.019 (314 hom.)
• Consequence: PTCH2 NM_003738.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.912

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-44827646-G-A is Benign according to our data. Variant chr1-44827646-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 415453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-44827646-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.912 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0142 (2158/152312) while in subpopulation NFE AF= 0.0232 (1578/68024). AF 95% confidence interval is 0.0222. There are 21 homozygotes in gnomad4. There are 1012 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2158 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH2	NM_003738.5	c.2127C>T	p.Asp709=	synonymous_variant	15/22	ENST00000372192.4
PTCH2	NM_001166292.2	c.2127C>T	p.Asp709=	synonymous_variant	15/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH2	ENST00000372192.4	c.2127C>T	p.Asp709=	synonymous_variant	15/22	1	NM_003738.5	P2
PTCH2	ENST00000447098.6	c.2127C>T	p.Asp709=	synonymous_variant	15/23	1		A2

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2158 AN: 152194 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0134 AC: 3324 AN: 248898 Hom.: 34 AF XY: 0.0138 AC XY: 1854 AN XY: 134776

Gnomad AFR exome AF: 0.00303

Gnomad AMR exome AF: 0.00868

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00601

Gnomad FIN exome AF: 0.00703

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0186 AC: 27180 AN: 1461030 Hom.: 314 Cov.: 37 AF XY: 0.0184 AC XY: 13340 AN XY: 726800

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.00877

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00588

Gnomad4 FIN exome AF: 0.00709

Gnomad4 NFE exome AF: 0.0217

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome AF: 0.0142 AC: 2158 AN: 152312 Hom.: 21 Cov.: 33 AF XY: 0.0136 AC XY: 1012 AN XY: 74482

Gnomad4 AFR AF: 0.00390

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00600

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0179 Hom.: 12

Bravo AF: 0.0135

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	3.5
Dann	Benign	0.87

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: rs11573587; hg19: chr1-45293318; COSMIC: COSV100942217; COSMIC: COSV100942217;