1-44823157-G-A

Variant names:

• chr1-44823157-G-A
• rs202184038
• NM_003738.5:c.3269C>T

Variant summary

Our verdict is Benign. The variant received -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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1090A) has been classified as Likely benign.

• 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:3
• Conservation: PhyloP100: 3.37
• Publications: 8 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: Benign. The variant received -8 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	NM_003738.5	MANE Select	c.3269C>T	p.Ala1090Val	missense	Exon 21 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.3269C>T	p.Ala1090Val	missense	Exon 21 of 23	NP_001159764.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	ENST00000372192.4	TSL:1 MANE Select	c.3269C>T	p.Ala1090Val	missense	Exon 21 of 22	ENSP00000361266.3
	PTCH2	ENST00000447098.7	TSL:1	c.3269C>T	p.Ala1090Val	missense	Exon 21 of 23	ENSP00000389703.2
	PTCH2	ENST00000881531.1		c.3218C>T	p.Ala1073Val	missense	Exon 21 of 22	ENSP00000551590.1

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

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 250814 AF XY: 0.000184

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 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

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000271 AC: 301 AN: 1111990

Other (OTH) AF: 0.000116 AC: 7 AN: 60388

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67994

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Basal cell carcinoma, susceptibility to, 1 (1)
-	1	-	Basal cell nevus syndrome 1 (1)
-	1	-	Gorlin syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.26
Sift	Benign	0.50	T
Sift4G	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.26
MVP		0.65
MPC		0.17
ClinPred		0.015	T
GERP RS		2.7
PromoterAI		0.0089	Neutral
Varity_R		0.043
gMVP		0.32
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs202184038; hg19: chr1-45288829; COSMIC: COSV63400187; COSMIC: COSV63400187;