rs139624405

Positions:

• chr1-44829624-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003738.5(PTCH2):​c.1073G>A​(p.Arg358His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 1,614,206 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R358C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0066 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (60 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.08

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010429025).
• BP6: Variant 1-44829624-C-T is Benign according to our data. Variant chr1-44829624-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-44829624-C-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 1006 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5	c.1073G>A	p.Arg358His	missense_variant	8/22	ENST00000372192.4	NP_003729.3
PTCH2	NM_001166292.2	c.1073G>A	p.Arg358His	missense_variant	8/23		NP_001159764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4	c.1073G>A	p.Arg358His	missense_variant	8/22	1	NM_003738.5	ENSP00000361266.3
PTCH2	ENST00000447098.6	c.1073G>A	p.Arg358His	missense_variant	8/23	1		ENSP00000389703.2

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 1006 AN: 152214 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00891

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00674 AC: 1694 AN: 251364 Hom.: 14 AF XY: 0.00647 AC XY: 879 AN XY: 135868

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.00955

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00747 AC: 10924 AN: 1461874 Hom.: 60 Cov.: 33 AF XY: 0.00724 AC XY: 5267 AN XY: 727242

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000939

Gnomad4 FIN exome AF: 0.0188

Gnomad4 NFE exome AF: 0.00841

Gnomad4 OTH exome AF: 0.00538

GnomAD4 genome AF: 0.00660 AC: 1006 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00698 AC XY: 520 AN XY: 74482

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.0197

Gnomad4 NFE AF: 0.00891

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00752 Hom.: 5

Bravo AF: 0.00515

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00721 AC: 875

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00735

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PTCH2 p.Arg358His variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs139624405), ClinVar (classified as benign by Invitae) and LOVD 3.0 (classified as likely benign and benign). The variant was identified in control databases in 1855 of 268230 chromosomes (14 homozygous) at a frequency of 0.006916 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 495 of 25108 chromosomes (freq: 0.01971), European (non-Finnish) in 1147 of 118078 chromosomes (freq: 0.009714), Other in 54 of 6704 chromosomes (freq: 0.008055), Latino in 84 of 35104 chromosomes (freq: 0.002393), African in 41 of 23610 chromosomes (freq: 0.001737), South Asian in 26 of 30524 chromosomes (freq: 0.000852) and Ashkenazi Jewish in 8 of 9856 chromosomes (freq: 0.000812), but was not observed in the East Asian population. The p.Arg358 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PTCH2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2021	- -

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.010	T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.2	L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.55
Sift	Benign	0.030	D;D
Sift4G	Benign	0.081	T;T
Polyphen		0.96	D;D
Vest4		0.21
MVP		0.98
MPC		0.54
ClinPred		0.033	T
GERP RS		5.0
Varity_R		0.084
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs139624405; hg19: chr1-45295296;