rs2066836

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_StrongBP7BA1

The NM_000264.5(PTCH1):c.1686C>T(p.Ala562Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,506 control chromosomes in the GnomAD database, including 33,080 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. A562A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 2388 hom., cov: 32)

Exomes 𝑓: 0.20 ( 30692 hom. )

Consequence

PTCH1
NM_000264.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -5.48

Publications

41 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:

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=-0.77).

BP6

Variant 9-95476076-G-A is Benign according to our data. Variant chr9-95476076-G-A is described in ClinVar as Benign. ClinVar VariationId is 255670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.48 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.1686C>T	p.Ala562Ala	synonymous_variant	Exon 12 of 24	ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 link	c.1683C>T	p.Ala561Ala	synonymous_variant	Exon 12 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.1686C>T	p.Ala562Ala	synonymous_variant	Exon 12 of 24	5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 link	c.1683C>T	p.Ala561Ala	synonymous_variant	Exon 12 of 24	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.154

AC:

23346

AN:

152046

Hom.:

2385

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0358

Gnomad AMI

AF:

0.189

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.270

Gnomad EAS

AF:

0.101

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.221

Gnomad OTH

AF:

0.166

GnomAD2 exomes

AF:

0.172

AC:

43045

AN:

250444

AF XY:

0.178

show subpopulations

Gnomad AFR exome

AF:

0.0309

Gnomad AMR exome

AF:

0.0870

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.104

Gnomad FIN exome

AF:

0.230

Gnomad NFE exome

AF:

0.218

Gnomad OTH exome

AF:

0.192

GnomAD4 exome

AF:

0.199

AC:

290845

AN:

1461342

Hom.:

30692

Cov.:

AF XY:

0.199

AC XY:

144598

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.0307

AC:

1028

AN:

33478

American (AMR)

AF:

0.0892

AC:

3989

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

6991

AN:

26126

East Asian (EAS)

AF:

0.0841

AC:

3339

AN:

39690

South Asian (SAS)

AF:

0.145

AC:

12529

AN:

86198

European-Finnish (FIN)

AF:

0.227

AC:

12101

AN:

53330

Middle Eastern (MID)

AF:

0.203

AC:

1169

AN:

5758

European-Non Finnish (NFE)

AF:

0.214

AC:

238438

AN:

1111696

Other (OTH)

AF:

0.187

AC:

11261

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

14896

29791

44687

59582

74478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7928

15856

23784

31712

39640

<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:

0.153

AC:

23345

AN:

152164

Hom.:

2388

Cov.:

AF XY:

0.153

AC XY:

11371

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0357

AC:

1482

AN:

41544

American (AMR)

AF:

0.108

AC:

1648

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

936

AN:

3472

East Asian (EAS)

AF:

0.101

AC:

519

AN:

5160

South Asian (SAS)

AF:

0.130

AC:

627

AN:

4806

European-Finnish (FIN)

AF:

0.241

AC:

2553

AN:

10600

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.221

AC:

15010

AN:

67972

Other (OTH)

AF:

0.164

AC:

346

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

962

1924

2885

3847

4809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.192

Hom.:

5094

Bravo

AF:

0.139

Asia WGS

AF:

0.0980

AC:

341

AN:

3478

EpiCase

AF:

0.222

EpiControl

AF:

0.225

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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.1686C>T (p.Ala562Ala) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing or ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 20642/118716 (2070 homozygotes, 1/5, frequency: 0.1738772), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PTCH1 variant of 1/58479 (0.0000171), suggesting this variant is likely a benign polymorphism. In addition, the variant has been indicated to co-occur with other pathogenic PTCH1 variants, c.2011_2012dup and c.3050_3051del, in affected individuals via publications. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Mar 03, 2015

GeneDx

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

- -

Jan 12, 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

May 04, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1+BP6+BP7 -

Dec 03, 2014

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. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holoprosencephaly 7

Benign:1

Jan 12, 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

-0.77

CADD

Benign

0.094

(source)

DANN

Benign

0.73

PhyloP100

-5.5

Mutation Taster

=96/4

polymorphism (auto)

(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