rs2066829

Positions:

• chr9-95467107-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000264.5(PTCH1):​c.2560+9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,613,226 control chromosomes in the GnomAD database, including 111,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15606 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95645 hom.)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.352

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]

LOC100507346 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 9-95467107-C-G is Benign according to our data. Variant chr9-95467107-C-G is described in ClinVar as [Benign]. Clinvar id is 255677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95467107-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.2560+9G>C		intron_variant		ENST00000331920.11
PTCH1	NM_001083603.3	c.2557+9G>C		intron_variant		ENST00000437951.6
LOC100507346	NR_038982.1	n.368C>G		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.2560+9G>C		intron_variant		5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.2557+9G>C		intron_variant		5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65163 AN: 151852 Hom.: 15553 Cov.: 32

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.386

GnomAD3 exomes AF: 0.347 AC: 87041 AN: 250766 Hom.: 16607 AF XY: 0.344 AC XY: 46595 AN XY: 135610

Gnomad AFR exome AF: 0.652

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.349

Gnomad SAS exome AF: 0.261

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.347

GnomAD4 exome AF: 0.356 AC: 520243 AN: 1461256 Hom.: 95645 Cov.: 41 AF XY: 0.354 AC XY: 257217 AN XY: 726946

Gnomad4 AFR exome AF: 0.654

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.416

Gnomad4 EAS exome AF: 0.321

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.372

Gnomad4 NFE exome AF: 0.360

Gnomad4 OTH exome AF: 0.360

GnomAD4 genome AF: 0.430 AC: 65279 AN: 151970 Hom.: 15606 Cov.: 32 AF XY: 0.422 AC XY: 31382 AN XY: 74278

Gnomad4 AFR AF: 0.644

Gnomad4 AMR AF: 0.258

Gnomad4 ASJ AF: 0.413

Gnomad4 EAS AF: 0.342

Gnomad4 SAS AF: 0.254

Gnomad4 FIN AF: 0.377

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.391

Alfa AF: 0.389 Hom.: 3886

Bravo AF: 0.431

Asia WGS AF: 0.328 AC: 1140 AN: 3478

EpiCase AF: 0.358

EpiControl AF: 0.363

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: The PTCH1 c.2560+9G>C variant involves the alteration of a non-conserved intronic nucleotide. 5/5 splice prediction tools predict no significant impact on normal splicing, however these predictions are yet to be confirmed by functional studies. This variant was found in 43313/120886 control chromosomes (8491 homozygotes) at an overall frequency of 0.3582962, which significantly exceeds the estimated maximal allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is a benign polymorphism. Taken together, based on the prevalence in the general population this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Holoprosencephaly 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.1
DANN	Benign	0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs2066829; hg19: chr9-98229389; COSMIC: COSV100109083; COSMIC: COSV100109083;