chr1-44828541-C-G

Variant names:

• chr1-44828541-C-G
• rs113543298
• NM_003738.5:c.1555G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003738.5(PTCH2):​c.1555G>C​(p.Val519Leu) 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. V519I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.77
• 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.1555G>C	p.Val519Leu	missense	Exon 12 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.1555G>C	p.Val519Leu	missense	Exon 12 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.1555G>C	p.Val519Leu	missense	Exon 12 of 22	ENSP00000361266.3
	PTCH2	ENST00000447098.7	TSL:1	c.1555G>C	p.Val519Leu	missense	Exon 12 of 23	ENSP00000389703.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.0	L
PhyloP100		2.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.60
Sift	Benign	0.069	T
Sift4G	Uncertain	0.039	D
Polyphen		0.0010	B
Vest4		0.57
MutPred		0.73		Loss of helix (P = 0.1706)
MVP		0.89
MPC		0.17
ClinPred		0.71	D
GERP RS		4.3
Varity_R		0.15
gMVP		0.78
Mutation Taster		=61/39	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: rs113543298; hg19: chr1-45294213;