rs11573585

Positions:

• chr1-44828412-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_003738.5(PTCH2):​c.1593G>A​(p.Ala531Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,614,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A531A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: PTCH2 NM_003738.5 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.27

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 -12 ACMG points.

• BP6: Variant 1-44828412-C-T is Benign according to our data. Variant chr1-44828412-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 453927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-44828412-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 159 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5	c.1593G>A	p.Ala531Ala	splice_region_variant, synonymous_variant	13/22	ENST00000372192.4	NP_003729.3
PTCH2	NM_001166292.2	c.1593G>A	p.Ala531Ala	splice_region_variant, synonymous_variant	13/23		NP_001159764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4	c.1593G>A	p.Ala531Ala	splice_region_variant, synonymous_variant	13/22	1	NM_003738.5	ENSP00000361266.3
PTCH2	ENST00000447098.6	c.1593G>A	p.Ala531Ala	splice_region_variant, synonymous_variant	13/23	1		ENSP00000389703.2

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000380 AC: 95 AN: 250316 Hom.: 0 AF XY: 0.000273 AC XY: 37 AN XY: 135366

Gnomad AFR exome AF: 0.00389

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000201 AC: 294 AN: 1461810 Hom.: 1 Cov.: 37 AF XY: 0.000202 AC XY: 147 AN XY: 727208

Gnomad4 AFR exome AF: 0.00442

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000773

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00106 AC XY: 79 AN XY: 74490

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000367 Hom.: 0

Bravo AF: 0.00118

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2020	- -

PTCH2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2019

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). -

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.4
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11573585; hg19: chr1-45294084;