NM_003738.5:c.1993C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_003738.5(PTCH2):c.1993C>T(p.Arg665Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R665H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

PTCH2
NM_003738.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter U:1B:2

Conservation

PhyloP100: 0.644

Publications

2 publications found

Variant links:

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]

PTCH2 Gene-Disease associations (from GenCC):

nevoid basal cell carcinoma syndrome
Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
commissural facial cleft
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PTCH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029508322).

BP6

Variant 1-44827908-G-A is Benign according to our data. Variant chr1-44827908-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 453930.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 80 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003738.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	NM_003738.5	MANE Select	c.1993C>T	p.Arg665Cys	missense	Exon 14 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.1993C>T	p.Arg665Cys	missense	Exon 14 of 23	NP_001159764.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PTCH2	ENST00000372192.4	TSL:1 MANE Select	c.1993C>T	p.Arg665Cys	missense	Exon 14 of 22	ENSP00000361266.3
PTCH2	ENST00000447098.7	TSL:1	c.1993C>T	p.Arg665Cys	missense	Exon 14 of 23	ENSP00000389703.2
PTCH2	ENST00000881531.1		c.1942C>T	p.Arg648Cys	missense	Exon 14 of 22	ENSP00000551590.1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000183

AC:

AN:

251308

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000155

AC:

226

AN:

1461842

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

105

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33480

American (AMR)

AF:

0.000335

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000138

AC:

153

AN:

1112010

Other (OTH)

AF:

0.000248

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000525

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

41578

American (AMR)

AF:

0.00105

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000252

Hom.:

Bravo

AF:

0.000540

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gorlin syndrome (1)

not provided (1)

PTCH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.67

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.030

MetaSVM

Benign

-0.36

MutationAssessor

Benign

0.97

PhyloP100

0.64

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.20

Sift

Benign

0.11

Sift4G

Pathogenic

0.0010

Polyphen

0.0

Vest4

0.084

MVP

0.76

MPC

0.23

ClinPred

0.014

GERP RS

2.9

Varity_R

0.11

gMVP

0.48

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over