chr1-44822420-C-A

Variant names:

• chr1-44822420-C-A
• rs369587910
• NM_003738.5:c.3607G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003738.5(PTCH2):​c.3607G>T​(p.Gly1203Trp) 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. 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. G1203R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.161
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.118582666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH2	NM_003738.5	c.3607G>T	p.Gly1203Trp	missense_variant	Exon 22 of 22	ENST00000372192.4	NP_003729.3
PTCH2	NM_001166292.2	c.3425+182G>T		intron_variant	Intron 22 of 22		NP_001159764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4	c.3607G>T	p.Gly1203Trp	missense_variant	Exon 22 of 22	1	NM_003738.5	ENSP00000361266.3
PTCH2	ENST00000447098.7	c.3425+182G>T		intron_variant	Intron 22 of 22	1		ENSP00000389703.2
PTCH2	ENST00000438067.5	c.185+182G>T		intron_variant	Intron 3 of 4	3		ENSP00000413169.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.55	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.16
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.46	P
Vest4		0.24
MutPred		0.26		Gain of solvent accessibility (P = 0.0062);
MVP		0.40
MPC		0.53
ClinPred		0.51	D
GERP RS		-0.27
Varity_R		0.12
gMVP		0.32
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs369587910; hg19: chr1-45288092;