rs11573598

Positions:

• chr1-44822664-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003738.5(PTCH2):​c.3363A>G​(p.Ile1121Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.883

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043581724).
• BP6: Variant 1-44822664-T-C is Benign according to our data. Variant chr1-44822664-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 415451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH2	NM_003738.5	c.3363A>G	p.Ile1121Met	missense_variant	22/22	ENST00000372192.4
PTCH2	NM_001166292.2	c.3363A>G	p.Ile1121Met	missense_variant	22/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH2	ENST00000372192.4	c.3363A>G	p.Ile1121Met	missense_variant	22/22	1	NM_003738.5	P2
PTCH2	ENST00000447098.6	c.3363A>G	p.Ile1121Met	missense_variant	22/23	1		A2
PTCH2	ENST00000438067.5	c.126A>G	p.Ile42Met	missense_variant	3/5	3

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000358 AC: 90 AN: 251210 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135774

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.000347

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: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000180 AC: 263 AN: 1461624 Hom.: 0 Cov.: 32 AF XY: 0.000158 AC XY: 115 AN XY: 727120

Gnomad4 AFR exome AF: 0.00615

Gnomad4 AMR exome AF: 0.000447

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: 0.0000108

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74404

Gnomad4 AFR AF: 0.00511

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000602 Hom.: 1

Bravo AF: 0.00163

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 11, 2021

- -

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 18, 2020

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	10
DANN	Benign	0.96
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.80	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.027	D;D
Sift4G	Uncertain	0.044	D;T
Polyphen		0.0	B;B
Vest4		0.10
MVP		0.84
MPC		0.17
ClinPred		0.0018	T
GERP RS		-2.8
Varity_R		0.11
gMVP		0.32

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: rs11573598; hg19: chr1-45288336; COSMIC: COSV100807989; COSMIC: COSV100807989;