1-44830004-A-G

Position:

• chr1-44830004-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003738.5(PTCH2):​c.840T>C​(p.Ser280Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,614,010 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (52 hom.)
• Consequence: PTCH2 NM_003738.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.32

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-44830004-A-G is Benign according to our data. Variant chr1-44830004-A-G is described in ClinVar as [Benign]. Clinvar id is 239562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-44830004-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.32 with no splicing effect.
• BS2: High AC in GnomAd4 at 788 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH2	NM_003738.5	c.840T>C	p.Ser280Ser	synonymous_variant	7/22	ENST00000372192.4	NP_003729.3
PTCH2	NM_001166292.2	c.840T>C	p.Ser280Ser	synonymous_variant	7/23		NP_001159764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000372192.4	c.840T>C	p.Ser280Ser	synonymous_variant	7/22	1	NM_003738.5	ENSP00000361266.3
PTCH2	ENST00000447098.6	c.840T>C	p.Ser280Ser	synonymous_variant	7/23	1		ENSP00000389703.2

Frequencies

GnomAD3 genomes AF: 0.00518 AC: 788 AN: 152082 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00676

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00535 AC: 1343 AN: 251018 Hom.: 12 AF XY: 0.00509 AC XY: 691 AN XY: 135746

Gnomad AFR exome AF: 0.000866

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00250

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.00693

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00640 AC: 9362 AN: 1461810 Hom.: 52 Cov.: 32 AF XY: 0.00632 AC XY: 4595 AN XY: 727198

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0133

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.0184

Gnomad4 NFE exome AF: 0.00666

Gnomad4 OTH exome AF: 0.00457

GnomAD4 genome AF: 0.00518 AC: 788 AN: 152200 Hom.: 4 Cov.: 33 AF XY: 0.00547 AC XY: 407 AN XY: 74438

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00677

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0172

Gnomad4 NFE AF: 0.00707

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00576 Hom.: 6

Bravo AF: 0.00372

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00439

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PTCH2: BP4, BP7, BS1, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

-

- -

Basal cell carcinoma, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.080
DANN	Benign	0.22

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: rs147627670; hg19: chr1-45295676;