rs2227970

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000264.5(PTCH1):c.2199A>G(p.Ser733Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,614,154 control chromosomes in the GnomAD database, including 224 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. S733S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 28 hom., cov: 32)

Exomes 𝑓: 0.016 ( 196 hom. )

Consequence

PTCH1
NM_000264.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -1.34

Publications

11 publications found

Variant links:

Genes affected

PTCH1 (HGNC:9585): (patched 1) This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]

PTCH1 Gene-Disease associations (from GenCC):

basal cell nevus syndrome 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
holoprosencephaly 7
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
nevoid basal cell carcinoma syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
holoprosencephaly
Inheritance: AD Classification: LIMITED Submitted by: Illumina

PTCH1 links:

LOC100507346 (HGNC:):

LOC100507346 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 9-95468802-T-C is Benign according to our data. Variant chr9-95468802-T-C is described in ClinVar as Benign. ClinVar VariationId is 132699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.34 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0118 (1797/152274) while in subpopulation EAS AF = 0.0307 (159/5182). AF 95% confidence interval is 0.0268. There are 28 homozygotes in GnomAd4. There are 922 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1797 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.2199A>G	p.Ser733Ser	synonymous_variant	Exon 14 of 24	ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 link	c.2196A>G	p.Ser732Ser	synonymous_variant	Exon 14 of 24	ENST00000437951.6	NP_001077072.1	Q13635-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11 link	c.2199A>G	p.Ser733Ser	synonymous_variant	Exon 14 of 24	5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 link	c.2196A>G	p.Ser732Ser	synonymous_variant	Exon 14 of 24	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1777

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00969

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.0308

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0145

AC:

3639

AN:

251494

AF XY:

0.0154

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00685

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.0290

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.0147

Gnomad OTH exome

AF:

0.0171

GnomAD4 exome

AF:

0.0157

AC:

22997

AN:

1461880

Hom.:

196

Cov.:

AF XY:

0.0158

AC XY:

11525

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

33480

American (AMR)

AF:

0.00698

AC:

312

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

352

AN:

26134

East Asian (EAS)

AF:

0.0252

AC:

999

AN:

39700

South Asian (SAS)

AF:

0.0190

AC:

1642

AN:

86258

European-Finnish (FIN)

AF:

0.0119

AC:

636

AN:

53420

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0161

AC:

17918

AN:

1112000

Other (OTH)

AF:

0.0164

AC:

992

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1480

2960

4441

5921

7401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

690

1380

2070

2760

3450

<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:

0.0118

AC:

1797

AN:

152274

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

922

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41552

American (AMR)

AF:

0.00967

AC:

148

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.0307

AC:

159

AN:

5182

South Asian (SAS)

AF:

0.0238

AC:

115

AN:

4826

European-Finnish (FIN)

AF:

0.0120

AC:

127

AN:

10610

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0152

AC:

1035

AN:

68012

Other (OTH)

AF:

0.0208

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

188

283

377

471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0127

Hom.:

Bravo

AF:

0.0106

Asia WGS

AF:

0.0550

AC:

190

AN:

3478

EpiCase

AF:

0.0156

EpiControl

AF:

0.0156

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 24, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PTCH1 c.2199A>G (p.Ser733Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant, 5/5 Alamut algorithms predict no change to splicing, and ESEfinder predicts the creation of exonic splice enhancers. However, these in silico predictions have not been validated by in vivo/vitro studies. This variant was found in 1767/121406 control chromosomes (21 homozygotes) at a frequency of 0.0145545, which is approximately 849 times the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), highly suggesting this variant is a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Based on the high prevalence in the general population, this variant was classified as Benign. -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 19, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gorlin syndrome

Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome

Benign:3

Feb 24, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Feb 17, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mar 25, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP7Supporting+BP6Supporting+BP4Supporting+BS2Strong+BS1Strong -

Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1;CN376810:Basal cell nevus syndrome 1

Benign:1

Aug 10, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holoprosencephaly 7

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.33

(source)

DANN

Benign

0.66

PhyloP100

-1.3

Mutation Taster

=100/0

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

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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