rs376337405

chr1-44830957-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003738.5(PTCH2):c.704G>A(p.Arg235Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000429 in 1,610,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R235W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.84

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21974927).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH2	NM_003738.5	c.704G>A	p.Arg235Gln	missense_variant	6/22	ENST00000372192.4
PTCH2	NM_001166292.2	c.704G>A	p.Arg235Gln	missense_variant	6/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH2	ENST00000372192.4	c.704G>A	p.Arg235Gln	missense_variant	6/22	1	NM_003738.5	P2
PTCH2	ENST00000447098.6	c.704G>A	p.Arg235Gln	missense_variant	6/23	1		A2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152148 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250364 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135480

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000412 AC: 60 AN: 1458038 Hom.: 0 Cov.: 31 AF XY: 0.0000400 AC XY: 29 AN XY: 724774

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000487

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152148 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74316

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 235 of the PTCH2 protein (p.Arg235Gln). This variant is present in population databases (rs376337405, gnomAD 0.01%). 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: 581418). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PTCH2 protein function with a negative predictive value of 80%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 22, 2023	The PTCH2 c.704G>A (p.Arg235Gln) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with nevoid basal cell carcinoma syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	0.026	D
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.91	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.13	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.27	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.98	.;D
Vest4		0.14
MVP		0.91
MPC		0.20
ClinPred		0.43	T
GERP RS		4.8
Varity_R		0.054
gMVP		0.52

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: rs376337405; hg19: chr1-45296629;