chr1-44821874-A-G

Variant names:

• chr1-44821874-A-G
• rs147018154
• ENST00000447098.7:c.3425+728T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The ENST00000438067.5(PTCH2):​c.216T>C​(p.Tyr72Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00604 in 1,365,722 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (19 hom.)
• Consequence: PTCH2 ENST00000438067.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.194
• Publications: 0 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

LOC107984952 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-44821874-A-G is Benign according to our data. Variant chr1-44821874-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2638779.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.194 with no splicing effect.
• BS2: High AC in GnomAd4 at 687 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC107984952	XR_001738036.3	n.728A>G		non_coding_transcript_exon_variant	Exon 2 of 2
PTCH2	NM_001166292.2	c.3425+728T>C		intron_variant	Intron 22 of 22		NP_001159764.1
PTCH2	NM_003738.5	c.*541T>C		downstream_gene_variant		ENST00000372192.4	NP_003729.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH2	ENST00000447098.7	c.3425+728T>C		intron_variant	Intron 22 of 22	1		ENSP00000389703.2
PTCH2	ENST00000438067.5	c.216T>C	p.Tyr72Tyr	synonymous_variant	Exon 4 of 5	3		ENSP00000413169.1
PTCH2	ENST00000372192.4	c.*541T>C		downstream_gene_variant		1	NM_003738.5	ENSP00000361266.3

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 686 AN: 152156 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00665

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00430 AC: 1030 AN: 239512 AF XY: 0.00430

Gnomad AFR exome AF: 0.000784

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00612

Gnomad OTH exome AF: 0.00455

GnomAD4 exome AF: 0.00623 AC: 7564 AN: 1213448 Hom.: 19 Cov.: 31 AF XY: 0.00598 AC XY: 3597 AN XY: 601250

African (AFR) AF: 0.000875 AC: 23 AN: 26274

American (AMR) AF: 0.00215 AC: 80 AN: 37202

Ashkenazi Jewish (ASJ) AF: 0.000178 AC: 3 AN: 16866

East Asian (EAS) AF: 0.00 AC: 0 AN: 16812

South Asian (SAS) AF: 0.000495 AC: 41 AN: 82852

European-Finnish (FIN) AF: 0.0128 AC: 401 AN: 31434

Middle Eastern (MID) AF: 0.000447 AC: 2 AN: 4476

European-Non Finnish (NFE) AF: 0.00712 AC: 6788 AN: 953560

Other (OTH) AF: 0.00514 AC: 226 AN: 43972

GnomAD4 genome AF: 0.00451 AC: 687 AN: 152274 Hom.: 3 Cov.: 32 AF XY: 0.00438 AC XY: 326 AN XY: 74452

African (AFR) AF: 0.00147 AC: 61 AN: 41558

American (AMR) AF: 0.00216 AC: 33 AN: 15292

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00666 AC: 453 AN: 68008

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00561 Hom.: 1

Bravo AF: 0.00353

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTCH2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.58
DANN	Benign	0.76
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs147018154; hg19: chr1-45287546;