rs147627670

Positions:

• chr1-44830004-A-C
• chr1-44830004-A-G
• chr1-44830004-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003738.5(PTCH2):​c.840T>G​(p.Ser280Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S280S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14043361).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5	c.840T>G	p.Ser280Arg	missense_variant	7/22	ENST00000372192.4	NP_003729.3
PTCH2	NM_001166292.2	c.840T>G	p.Ser280Arg	missense_variant	7/23		NP_001159764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4	c.840T>G	p.Ser280Arg	missense_variant	7/22	1	NM_003738.5	ENSP00000361266	P2
PTCH2	ENST00000447098.6	c.840T>G	p.Ser280Arg	missense_variant	7/23	1		ENSP00000389703	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.0070
DANN	Benign	0.72
DEOGEN2	Uncertain	0.44	.;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.4	N;N
REVEL	Benign	0.26
Sift	Benign	0.063	T;T
Sift4G	Uncertain	0.052	T;T
Polyphen		0.058	.;B
Vest4		0.22
MutPred		0.49		Loss of glycosylation at S280 (P = 0.0192);Loss of glycosylation at S280 (P = 0.0192);
MVP		0.51
MPC		0.19
ClinPred		0.14	T
GERP RS		-9.3
Varity_R		0.13
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147627670; hg19: chr1-45295676;