1-44827512-C-A

Position:

• chr1-44827512-C-A

Variant summary

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

The ENST00000372192.4(PTCH2):​c.2261G>T​(p.Arg754Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R754H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH2 ENST00000372192.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.38

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5	c.2261G>T	p.Arg754Leu	missense_variant	15/22	ENST00000372192.4	NP_003729.3
PTCH2	NM_001166292.2	c.2261G>T	p.Arg754Leu	missense_variant	15/23		NP_001159764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4	c.2261G>T	p.Arg754Leu	missense_variant	15/22	1	NM_003738.5	ENSP00000361266.3
PTCH2	ENST00000447098.6	c.2261G>T	p.Arg754Leu	missense_variant	15/23	1		ENSP00000389703.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251016 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.89	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.015	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.74	P;B
Vest4		0.60
MutPred		0.69		Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);
MVP		0.88
MPC		0.24
ClinPred		0.82	D
GERP RS		3.9
Varity_R		0.27
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs757344433; hg19: chr1-45293184;