rs34245589

chr1-44827032-G-A

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.2565C>T(p.Leu855=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,126 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (85 hom.)
• Consequence: PTCH2 NM_003738.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.216

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=-0.55).
• BP6: Variant 1-44827032-G-A is Benign according to our data. Variant chr1-44827032-G-A is described in ClinVar as [Benign]. Clinvar id is 239558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.216 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00416 (634/152326) while in subpopulation AMR AF= 0.0373 (571/15298). AF 95% confidence interval is 0.0348. There are 20 homozygotes in gnomad4. There are 336 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 631 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH2	NM_003738.5	c.2565C>T	p.Leu855=	synonymous_variant	17/22	ENST00000372192.4
PTCH2	NM_001166292.2	c.2565C>T	p.Leu855=	synonymous_variant	17/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH2	ENST00000372192.4	c.2565C>T	p.Leu855=	synonymous_variant	17/22	1	NM_003738.5	P2
PTCH2	ENST00000447098.6	c.2565C>T	p.Leu855=	synonymous_variant	17/23	1		A2

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 631 AN: 152208 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00715 AC: 1797 AN: 251420 Hom.: 70 AF XY: 0.00526 AC XY: 715 AN XY: 135894

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0501

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00651

GnomAD4 exome AF: 0.00168 AC: 2457 AN: 1461800 Hom.: 85 Cov.: 34 AF XY: 0.00139 AC XY: 1014 AN XY: 727204

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.0506

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00416 AC: 634 AN: 152326 Hom.: 20 Cov.: 33 AF XY: 0.00451 AC XY: 336 AN XY: 74488

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.0373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.00667

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome;C0025149:Medulloblastoma;C2751544:Basal cell carcinoma, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 04, 2022

- -

PTCH2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2019

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

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	3.4
Dann	Benign	0.78

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: rs34245589; hg19: chr1-45292704;