1-44822479-C-A

Position:

• chr1-44822479-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_003738.5(PTCH2):​c.3548G>T​(p.Trp1183Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18381295).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5	c.3548G>T	p.Trp1183Leu	missense_variant	22/22	ENST00000372192.4	NP_003729.3
PTCH2	NM_001166292.2	c.3425+123G>T		intron_variant			NP_001159764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4	c.3548G>T	p.Trp1183Leu	missense_variant	22/22	1	NM_003738.5	ENSP00000361266	P2
PTCH2	ENST00000447098.6	c.3425+123G>T		intron_variant		1		ENSP00000389703	A2
PTCH2	ENST00000438067.5	c.186+123G>T		intron_variant		3		ENSP00000413169

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250514 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461654 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727118

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.39	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.61	T
Polyphen		0.18	B
Vest4		0.37
MutPred		0.21		Loss of glycosylation at P1181 (P = 0.1413);
MVP		0.90
MPC		0.53
ClinPred		0.14	T
GERP RS		2.6
Varity_R		0.19
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs56024410; hg19: chr1-45288151;