1-44828412-C-T

Variant names:

• chr1-44828412-C-T
• rs11573585
• NM_003738.5:c.1593G>A

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.1593G>A​(p.Ala531Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,614,128 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A531A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: PTCH2 NM_003738.5 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.27
• 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: 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

ACMG classification

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

• BP6: Variant 1-44828412-C-T is Benign according to our data. Variant chr1-44828412-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 453927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 159 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.1593G>A	p.Ala531Ala	splice_region synonymous	Exon 13 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.1593G>A	p.Ala531Ala	splice_region synonymous	Exon 13 of 23	NP_001159764.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	ENST00000372192.4	TSL:1 MANE Select	c.1593G>A	p.Ala531Ala	splice_region synonymous	Exon 13 of 22	ENSP00000361266.3
	PTCH2	ENST00000447098.7	TSL:1	c.1593G>A	p.Ala531Ala	splice_region synonymous	Exon 13 of 23	ENSP00000389703.2
	PTCH2	ENST00000881531.1		c.1542G>A	p.Ala514Ala	splice_region synonymous	Exon 13 of 22	ENSP00000551590.1

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000380 AC: 95 AN: 250316 AF XY: 0.000273

Gnomad AFR exome AF: 0.00389

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000201 AC: 294 AN: 1461810 Hom.: 1 Cov.: 37 AF XY: 0.000202 AC XY: 147 AN XY: 727208

African (AFR) AF: 0.00442 AC: 148 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86254

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53360

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000773 AC: 86 AN: 1112000

Other (OTH) AF: 0.000364 AC: 22 AN: 60392

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00106 AC XY: 79 AN XY: 74490

African (AFR) AF: 0.00308 AC: 128 AN: 41562

American (AMR) AF: 0.000849 AC: 13 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.00118

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Gorlin syndrome (1)
-	-	1	PTCH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.4
DANN	Benign	0.73
PhyloP100		-4.3
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: -2

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

Other links and lift over

dbSNP: rs11573585; hg19: chr1-45294084;