rs45573433

Variant names:

• chr1-44842022-C-T
• rs45573433
• NM_003738.5:c.90G>A
• PTCH2 p.Leu30Leu

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_003738.5(PTCH2):​c.90G>A​(p.Leu30Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,006 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (10 hom., cov: 32)
  • Exomes 𝑓: 0.012 (117 hom.)
• Consequence: PTCH2 NM_003738.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.686
• Publications: 5 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), Genomics England PanelApp, Orphanet, ClinGen
• commissural facial cleft

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 1-44842022-C-T is Benign according to our data. Variant chr1-44842022-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1400 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.90G>A	p.Leu30Leu	synonymous	Exon 2 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.90G>A	p.Leu30Leu	synonymous	Exon 2 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.90G>A	p.Leu30Leu	synonymous	Exon 2 of 22	ENSP00000361266.3	Q9Y6C5-1
	PTCH2	ENST00000447098.7	TSL:1	c.90G>A	p.Leu30Leu	synonymous	Exon 2 of 23	ENSP00000389703.2	Q9Y6C5-2
	PTCH2	ENST00000881531.1		c.73-34G>A		intron	N/A	ENSP00000551590.1

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 1400 AN: 152216 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.0101 AC: 2530 AN: 251390 AF XY: 0.0103

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00413

Gnomad ASJ exome AF: 0.00982

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0120 AC: 17557 AN: 1460672 Hom.: 117 Cov.: 33 AF XY: 0.0118 AC XY: 8546 AN XY: 726712

African (AFR) AF: 0.00188 AC: 63 AN: 33440

American (AMR) AF: 0.00454 AC: 203 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 297 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00290 AC: 250 AN: 86226

European-Finnish (FIN) AF: 0.0274 AC: 1462 AN: 53418

Middle Eastern (MID) AF: 0.00685 AC: 38 AN: 5546

European-Non Finnish (NFE) AF: 0.0132 AC: 14655 AN: 1111162

Other (OTH) AF: 0.00975 AC: 588 AN: 60330

GnomAD4 genome AF: 0.00919 AC: 1400 AN: 152334 Hom.: 10 Cov.: 32 AF XY: 0.00995 AC XY: 741 AN XY: 74488

African (AFR) AF: 0.00253 AC: 105 AN: 41578

American (AMR) AF: 0.00654 AC: 100 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.0297 AC: 316 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 805 AN: 68018

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.0111 Hom.: 9

Bravo AF: 0.00738

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0135

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Basal cell carcinoma, susceptibility to, 1 (1)
-	-	1	Basal cell nevus syndrome 1 (1)
-	-	1	Gorlin syndrome (1)
-	-	1	Medulloblastoma;C2751544:Basal cell carcinoma, susceptibility to, 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.79
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs45573433;

hg19: chr1-45307694;

COSMIC: COSV64710056;