rs747885797

Variant names:

• chr1-44831758-G-A
• rs747885797
• NM_003738.5:c.565C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-44831758-G-A
• chr1-44831758-G-C
• chr1-44831758-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_003738.5(PTCH2):​c.565C>T​(p.Leu189Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,586,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L189I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51
• Publications: 1 publications found

Genes affected

PTCH2 (HGNC:9586): (patched 2) This gene encodes a transmembrane receptor of the patched gene family. The encoded protein may function as a tumor suppressor in the hedgehog signaling pathway. Alterations in this gene have been associated with nevoid basal cell carcinoma syndrome, basal cell carcinoma, medulloblastoma, and susceptibility to congenital macrostomia. Alternatively spliced transcript variants have been described.[provided by RefSeq, Oct 2009]

PTCH2 Gene-Disease associations (from GenCC):

• nevoid basal cell carcinoma syndrome

  Inheritance: Unknown, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp
• commissural facial cleft

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82
• BS2: High AC in GnomAdExome4 at 6 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003738.5. 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
	PTCH2	NM_003738.5	MANE Select	c.565C>T	p.Leu189Phe	missense	Exon 5 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.565C>T	p.Leu189Phe	missense	Exon 5 of 23	NP_001159764.1	Q9Y6C5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	ENST00000372192.4	TSL:1 MANE Select	c.565C>T	p.Leu189Phe	missense	Exon 5 of 22	ENSP00000361266.3	Q9Y6C5-1
	PTCH2	ENST00000447098.7	TSL:1	c.565C>T	p.Leu189Phe	missense	Exon 5 of 23	ENSP00000389703.2	Q9Y6C5-2
	PTCH2	ENST00000881531.1		c.514C>T	p.Leu172Phe	missense	Exon 5 of 22	ENSP00000551590.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000418 AC: 6 AN: 1434582 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 711478

African (AFR) AF: 0.00 AC: 0 AN: 32720

American (AMR) AF: 0.00 AC: 0 AN: 39912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25554

East Asian (EAS) AF: 0.0000528 AC: 2 AN: 37880

South Asian (SAS) AF: 0.00 AC: 0 AN: 83122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1098478

Other (OTH) AF: 0.00 AC: 0 AN: 59424

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.48		Loss of sheet (P = 0.1158)
MVP		0.99
MPC		0.74
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.68
gMVP		0.88
Mutation Taster		=48/52	disease causing

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: rs747885797; hg19: chr1-45297430;