rs774219740

Variant names:

• chr1-44841883-T-C
• rs774219740
• NM_003738.5:c.229A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003738.5(PTCH2):​c.229A>G​(p.Ile77Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I77I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.754
• Publications: 0 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: AD, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• commissural facial cleft

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043468237).
• BS2: High AC in GnomAdExome4 at 34 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	NM_003738.5	MANE Select	c.229A>G	p.Ile77Val	missense	Exon 2 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.229A>G	p.Ile77Val	missense	Exon 2 of 23	NP_001159764.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	ENST00000372192.4	TSL:1 MANE Select	c.229A>G	p.Ile77Val	missense	Exon 2 of 22	ENSP00000361266.3
	PTCH2	ENST00000447098.7	TSL:1	c.229A>G	p.Ile77Val	missense	Exon 2 of 23	ENSP00000389703.2
	PTCH2	ENST00000881531.1		c.178A>G	p.Ile60Val	missense	Exon 2 of 22	ENSP00000551590.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251482 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1112008

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.41
DANN	Benign	0.61
DEOGEN2	Benign	0.076	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	-0.12	N
PhyloP100		-0.75
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.17
Sift	Benign	0.33	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.47		Loss of catalytic residue at L82 (P = 0.074)
MVP		0.79
MPC		0.14
ClinPred		0.083	T
GERP RS		-4.3
Varity_R		0.026
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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: rs774219740; hg19: chr1-45307555;