chr1-44826501-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003738.5(PTCH2):c.2963C>T(p.Thr988Met) variant causes a missense change. The variant allele was found at a frequency of 0.0299 in 1,613,816 control chromosomes in the GnomAD database, including 1,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T988T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.029 ( 187 hom., cov: 32)

Exomes 𝑓: 0.030 ( 1246 hom. )

Consequence

PTCH2
NM_003738.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.89

Publications

24 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020764172).

BP6

Variant 1-44826501-G-A is Benign according to our data. Variant chr1-44826501-G-A is described in ClinVar as Benign. ClinVar VariationId is 415448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH2	NM_003738.5 link	c.2963C>T	p.Thr988Met	missense_variant	Exon 18 of 22	ENST00000372192.4	NP_003729.3	Q9Y6C5-1
PTCH2	NM_001166292.2 link	c.2963C>T	p.Thr988Met	missense_variant	Exon 18 of 23		NP_001159764.1	Q9Y6C5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4 link	c.2963C>T	p.Thr988Met	missense_variant	Exon 18 of 22	1	NM_003738.5	ENSP00000361266.3		Q9Y6C5-1
PTCH2	ENST00000447098.7 link	c.2963C>T	p.Thr988Met	missense_variant	Exon 18 of 23	1		ENSP00000389703.2		Q9Y6C5-2

Frequencies

GnomAD3 genomes

AF:

0.0290

AC:

4406

AN:

152152

Hom.:

189

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00555

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0598

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.163

Gnomad SAS

AF:

0.0642

Gnomad FIN

AF:

0.0444

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0221

Gnomad OTH

AF:

0.0311

GnomAD2 exomes

AF:

0.0468

AC:

11675

AN:

249552

AF XY:

0.0449

show subpopulations

Gnomad AFR exome

AF:

0.00502

Gnomad AMR exome

AF:

0.0844

Gnomad ASJ exome

AF:

0.0247

Gnomad EAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.0463

Gnomad NFE exome

AF:

0.0210

Gnomad OTH exome

AF:

0.0357

GnomAD4 exome

AF:

0.0300

AC:

43779

AN:

1461546

Hom.:

1246

Cov.:

AF XY:

0.0304

AC XY:

22130

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.00460

AC:

154

AN:

33480

American (AMR)

AF:

0.0835

AC:

3733

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0237

AC:

620

AN:

26136

East Asian (EAS)

AF:

0.152

AC:

6040

AN:

39696

South Asian (SAS)

AF:

0.0595

AC:

5132

AN:

86252

European-Finnish (FIN)

AF:

0.0470

AC:

2502

AN:

53184

Middle Eastern (MID)

AF:

0.0304

AC:

175

AN:

5754

European-Non Finnish (NFE)

AF:

0.0208

AC:

23179

AN:

1111960

Other (OTH)

AF:

0.0372

AC:

2244

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2868

5737

8605

11474

14342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1010

2020

3030

4040

5050

<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:

0.0290

AC:

4419

AN:

152270

Hom.:

187

Cov.:

AF XY:

0.0315

AC XY:

2343

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00553

AC:

230

AN:

41554

American (AMR)

AF:

0.0601

AC:

920

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3470

East Asian (EAS)

AF:

0.164

AC:

847

AN:

5176

South Asian (SAS)

AF:

0.0643

AC:

310

AN:

4822

European-Finnish (FIN)

AF:

0.0444

AC:

471

AN:

10614

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0221

AC:

1500

AN:

68016

Other (OTH)

AF:

0.0346

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

204

408

611

815

1019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0253

Hom.:

384

Bravo

AF:

0.0286

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0207

AC:

178

ExAC

AF:

0.0436

AC:

5295

Asia WGS

AF:

0.102

AC:

355

AN:

3478

EpiCase

AF:

0.0210

EpiControl

AF:

0.0176

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 04, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Basal cell carcinoma, susceptibility to, 1

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gorlin syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Basal cell nevus syndrome 1

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

.;T

Eigen

Benign

-0.069

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.85

D;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

3.9

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.031

D;D

Sift4G

Benign

0.093

T;T

Polyphen

0.84

P;P

Vest4

0.20

MPC

0.19

ClinPred

0.027

GERP RS

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.091

gMVP

0.79

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over