rs2236406

Variant names:

• chr9-95459579-T-C
• rs2236406
• NM_000264.5:c.2887+21A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-95459579-T-C
• chr9-95459579-T-A

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.2887+21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,611,910 control chromosomes in the GnomAD database, including 108,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15811 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92990 hom.)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.517
• Publications: 18 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-95459579-T-C is Benign according to our data. Variant chr9-95459579-T-C is described in ClinVar as Benign. ClinVar VariationId is 255678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.653 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.2887+21A>G		intron	N/A	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.2884+21A>G		intron	N/A	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.2731+21A>G		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.2887+21A>G		intron	N/A	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.2884+21A>G		intron	N/A	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.2434+21A>G		intron	N/A	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65179 AN: 151984 Hom.: 15755 Cov.: 32

Gnomad AFR AF: 0.659

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.382

GnomAD2 exomes AF: 0.345 AC: 86510 AN: 251098 AF XY: 0.340

Gnomad AFR exome AF: 0.669

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.352

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.351 AC: 511954 AN: 1459806 Hom.: 92990 Cov.: 37 AF XY: 0.349 AC XY: 253153 AN XY: 726250

African (AFR) AF: 0.670 AC: 22374 AN: 33410

American (AMR) AF: 0.187 AC: 8383 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10826 AN: 26132

East Asian (EAS) AF: 0.326 AC: 12952 AN: 39692

South Asian (SAS) AF: 0.263 AC: 22675 AN: 86174

European-Finnish (FIN) AF: 0.369 AC: 19713 AN: 53402

Middle Eastern (MID) AF: 0.346 AC: 1590 AN: 4594

European-Non Finnish (NFE) AF: 0.353 AC: 392097 AN: 1111466

Other (OTH) AF: 0.354 AC: 21344 AN: 60220

GnomAD4 genome AF: 0.429 AC: 65300 AN: 152104 Hom.: 15811 Cov.: 32 AF XY: 0.422 AC XY: 31408 AN XY: 74352

African (AFR) AF: 0.660 AC: 27371 AN: 41482

American (AMR) AF: 0.252 AC: 3850 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1432 AN: 3470

East Asian (EAS) AF: 0.348 AC: 1799 AN: 5168

South Asian (SAS) AF: 0.253 AC: 1220 AN: 4816

European-Finnish (FIN) AF: 0.375 AC: 3961 AN: 10570

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24540 AN: 67988

Other (OTH) AF: 0.388 AC: 821 AN: 2116

Alfa AF: 0.401 Hom.: 2370

Bravo AF: 0.431

Asia WGS AF: 0.333 AC: 1158 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.32
PhyloP100		-0.52
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: rs2236406; hg19: chr9-98221861; COSMIC: COSV59491220;