chr1-44823157-G-A

Position:

• chr1-44823157-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003738.5(PTCH2):​c.3269C>T​(p.Ala1090Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.37

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05075839).
• BS2: High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5	c.3269C>T	p.Ala1090Val	missense_variant	21/22	ENST00000372192.4	NP_003729.3
PTCH2	NM_001166292.2	c.3269C>T	p.Ala1090Val	missense_variant	21/23		NP_001159764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4	c.3269C>T	p.Ala1090Val	missense_variant	21/22	1	NM_003738.5	ENSP00000361266	P2
PTCH2	ENST00000447098.6	c.3269C>T	p.Ala1090Val	missense_variant	21/23	1		ENSP00000389703	A2
PTCH2	ENST00000438067.5	c.32C>T	p.Ala11Val	missense_variant	2/5	3		ENSP00000413169

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 250814 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135666

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000217 AC: 317 AN: 1461824 Hom.: 0 Cov.: 33 AF XY: 0.000234 AC XY: 170 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000271

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74440

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.000313 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Basal cell carcinoma, susceptibility to, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 23, 2023

- -

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 26, 2023

This variant has not been reported in the literature in individuals affected with PTCH2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PTCH2 protein function. ClinVar contains an entry for this variant (Variation ID: 453937). This variant is present in population databases (rs202184038, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1090 of the PTCH2 protein (p.Ala1090Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.65
DEOGEN2	Benign	0.14	.;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.70	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.23	N;N
REVEL	Benign	0.26
Sift	Benign	0.50	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.0010	B;B
Vest4		0.26
MVP		0.65
MPC		0.17
ClinPred		0.015	T
GERP RS		2.7
Varity_R		0.043
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs202184038; hg19: chr1-45288829; COSMIC: COSV63400187; COSMIC: COSV63400187;