rs187485698

Variant names:

• chr1-44829149-T-C
• rs187485698
• NM_003738.5:c.1371+8A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003738.5(PTCH2):​c.1371+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,613,816 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (11 hom.)
• Consequence: PTCH2 NM_003738.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002683
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.169
• 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, Orphanet, Labcorp Genetics (formerly Invitae)
• commissural facial cleft

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-44829149-T-C is Benign according to our data. Variant chr1-44829149-T-C is described in ClinVar as Benign. ClinVar VariationId is 415459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00607 (924/152342) while in subpopulation AFR AF = 0.0208 (867/41584). AF 95% confidence interval is 0.0197. There are 12 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 924 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.1371+8A>G		splice_region intron	N/A	NP_003729.3
	PTCH2	NM_001166292.2		c.1371+8A>G		splice_region intron	N/A	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.1371+8A>G		splice_region intron	N/A	ENSP00000361266.3	Q9Y6C5-1
	PTCH2	ENST00000447098.7	TSL:1	c.1371+8A>G		splice_region intron	N/A	ENSP00000389703.2	Q9Y6C5-2
	PTCH2	ENST00000881531.1		c.1320+8A>G		splice_region intron	N/A	ENSP00000551590.1

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 919 AN: 152224 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00151 AC: 379 AN: 250496 AF XY: 0.000907

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000624 AC: 912 AN: 1461474 Hom.: 11 Cov.: 32 AF XY: 0.000484 AC XY: 352 AN XY: 727056

African (AFR) AF: 0.0223 AC: 746 AN: 33476

American (AMR) AF: 0.00101 AC: 45 AN: 44716

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

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.000703 AC: 4 AN: 5690

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111996

Other (OTH) AF: 0.00154 AC: 93 AN: 60388

GnomAD4 genome AF: 0.00607 AC: 924 AN: 152342 Hom.: 12 Cov.: 33 AF XY: 0.00616 AC XY: 459 AN XY: 74500

African (AFR) AF: 0.0208 AC: 867 AN: 41584

American (AMR) AF: 0.00294 AC: 45 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00649 Hom.: 9

Bravo AF: 0.00751

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Basal cell carcinoma, susceptibility to, 1 (1)
-	-	1	Basal cell nevus syndrome 1 (1)
-	-	1	Gorlin syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.76
DANN	Benign	0.46
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.040
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

Other links and lift over

dbSNP: rs187485698; hg19: chr1-45294821;