NM_003738.5:c.2782G>A

Variant names:

• chr1-44826682-C-T
• rs199998309
• NM_003738.5:c.2782G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_003738.5(PTCH2):​c.2782G>A​(p.Glu928Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000213 in 1,607,508 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.80
• Publications: 2 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: Unknown, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp
• commissural facial cleft

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07000625).
• BP6: Variant 1-44826682-C-T is Benign according to our data. Variant chr1-44826682-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 415450.
• BS2: High AC in GnomAd4 at 26 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.2782G>A	p.Glu928Lys	missense	Exon 18 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.2782G>A	p.Glu928Lys	missense	Exon 18 of 23	NP_001159764.1	Q9Y6C5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	ENST00000372192.4	TSL:1 MANE Select	c.2782G>A	p.Glu928Lys	missense	Exon 18 of 22	ENSP00000361266.3	Q9Y6C5-1
	PTCH2	ENST00000447098.7	TSL:1	c.2782G>A	p.Glu928Lys	missense	Exon 18 of 23	ENSP00000389703.2	Q9Y6C5-2
	PTCH2	ENST00000881531.1		c.2731G>A	p.Glu911Lys	missense	Exon 18 of 22	ENSP00000551590.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000424 AC: 102 AN: 240764 AF XY: 0.000365

Gnomad AFR exome AF: 0.000471

Gnomad AMR exome AF: 0.0000889

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000479

Gnomad NFE exome AF: 0.000722

Gnomad OTH exome AF: 0.000342

GnomAD4 exome AF: 0.000217 AC: 316 AN: 1455226 Hom.: 1 Cov.: 34 AF XY: 0.000202 AC XY: 146 AN XY: 723262

African (AFR) AF: 0.000330 AC: 11 AN: 33344

American (AMR) AF: 0.0000681 AC: 3 AN: 44070

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85726

European-Finnish (FIN) AF: 0.000286 AC: 15 AN: 52470

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5706

European-Non Finnish (NFE) AF: 0.000227 AC: 252 AN: 1108516

Other (OTH) AF: 0.000466 AC: 28 AN: 60042

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74446

African (AFR) AF: 0.000337 AC: 14 AN: 41560

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000381 Hom.: 1

Bravo AF: 0.000140

ExAC AF: 0.000652 AC: 79

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Basal cell carcinoma, susceptibility to, 1 (1)
-	-	1	Gorlin syndrome (1)
-	1	-	not specified (1)
-	-	1	PTCH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.070	T
MetaSVM	Uncertain	-0.077	T
MutationAssessor	Benign	-0.35	N
PhyloP100		3.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.54
Sift	Benign	0.49	T
Sift4G	Benign	0.41	T
Polyphen		0.55	P
Vest4		0.39
MVP		0.89
MPC		0.20
ClinPred		0.015	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.78
Mutation Taster		=58/42	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: rs199998309; hg19: chr1-45292354;