9-95476076-G-A

Variant names:

• chr9-95476076-G-A
• rs2066836
• NM_000264.5:c.1686C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -5.48
• Publications: 41 publications found

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

ACMG classification

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	c.1686C>T	p.Ala562Ala	synonymous_variant	Exon 12 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.1683C>T	p.Ala561Ala	synonymous_variant	Exon 12 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23346 AN: 152046 Hom.: 2385 Cov.: 32

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

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.: 35 AF XY: 0.199 AC XY: 144598 AN XY: 726946

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

GnomAD4 genome AF: 0.153 AC: 23345 AN: 152164 Hom.: 2388 Cov.: 32 AF XY: 0.153 AC XY: 11371 AN XY: 74394

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: 52 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15010 AN: 67972

Other (OTH) AF: 0.164 AC: 346 AN: 2114

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

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.094
DANN	Benign	0.73
PhyloP100		-5.5
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2066836; hg19: chr9-98238358; COSMIC: COSV59461212; COSMIC: COSV59461212;