NM_000264.5:c.2560+9G>C

Variant names:

• chr9-95467107-C-G
• rs2066829
• NM_000264.5:c.2560+9G>C

Variant summary

Our verdict is Benign. The variant received -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:11
• Conservation: PhyloP100: 0.352
• Publications: 22 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, Orphanet, Labcorp Genetics (formerly Invitae)
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

LOC100507346 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 255677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000264.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.2560+9G>C		intron	N/A	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.2557+9G>C		intron	N/A	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.2404+9G>C		intron	N/A	NP_001341847.1	A0A1W5YLI7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.2560+9G>C		intron	N/A	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.2557+9G>C		intron	N/A	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.2107+9G>C		intron	N/A	ENSP00000414823.2	Q13635-4

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

GnomAD2 exomes AF: 0.347 AC: 87041 AN: 250766 AF XY: 0.344

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 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

African (AFR) AF: 0.654 AC: 21880 AN: 33462

American (AMR) AF: 0.192 AC: 8579 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 10869 AN: 26126

East Asian (EAS) AF: 0.321 AC: 12752 AN: 39690

South Asian (SAS) AF: 0.265 AC: 22840 AN: 86228

European-Finnish (FIN) AF: 0.372 AC: 19879 AN: 53420

Middle Eastern (MID) AF: 0.346 AC: 1994 AN: 5764

European-Non Finnish (NFE) AF: 0.360 AC: 399728 AN: 1111486

Other (OTH) AF: 0.360 AC: 21722 AN: 60370

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

African (AFR) AF: 0.644 AC: 26666 AN: 41428

American (AMR) AF: 0.258 AC: 3945 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1434 AN: 3470

East Asian (EAS) AF: 0.342 AC: 1769 AN: 5168

South Asian (SAS) AF: 0.254 AC: 1222 AN: 4818

European-Finnish (FIN) AF: 0.377 AC: 3971 AN: 10534

Middle Eastern (MID) AF: 0.342 AC: 100 AN: 292

European-Non Finnish (NFE) AF: 0.367 AC: 24966 AN: 67966

Other (OTH) AF: 0.391 AC: 824 AN: 2106

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Gorlin syndrome (4)
-	-	3	not provided (3)
-	-	2	Holoprosencephaly 7 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.1
DANN	Benign	0.20
PhyloP100		0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs2066829; hg19: chr9-98229389; COSMIC: COSV100109083;