rs11573587

Variant names:

• chr1-44827646-G-A
• rs11573587
• NM_003738.5:c.2127C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-44827646-G-A
• chr1-44827646-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003738.5(PTCH2):​c.2127C>T​(p.Asp709Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,613,342 control chromosomes in the GnomAD database, including 335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (21 hom., cov: 33)
  • Exomes 𝑓: 0.019 (314 hom.)
• Consequence: PTCH2 NM_003738.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.912
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-44827646-G-A is Benign according to our data. Variant chr1-44827646-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.912 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2158/152312) while in subpopulation NFE AF = 0.0232 (1578/68024). AF 95% confidence interval is 0.0222. There are 21 homozygotes in GnomAd4. There are 1012 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2158 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.2127C>T	p.Asp709Asp	synonymous	Exon 15 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.2127C>T	p.Asp709Asp	synonymous	Exon 15 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.2127C>T	p.Asp709Asp	synonymous	Exon 15 of 22	ENSP00000361266.3
	PTCH2	ENST00000447098.7	TSL:1	c.2127C>T	p.Asp709Asp	synonymous	Exon 15 of 23	ENSP00000389703.2
	PTCH2	ENST00000881531.1		c.2076C>T	p.Asp692Asp	synonymous	Exon 15 of 22	ENSP00000551590.1

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2158 AN: 152194 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0134 AC: 3324 AN: 248898 AF XY: 0.0138

Gnomad AFR exome AF: 0.00303

Gnomad AMR exome AF: 0.00868

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00703

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0186 AC: 27180 AN: 1461030 Hom.: 314 Cov.: 37 AF XY: 0.0184 AC XY: 13340 AN XY: 726800

African (AFR) AF: 0.00251 AC: 84 AN: 33480

American (AMR) AF: 0.00877 AC: 392 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 728 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00588 AC: 507 AN: 86256

European-Finnish (FIN) AF: 0.00709 AC: 373 AN: 52602

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0217 AC: 24078 AN: 1111982

Other (OTH) AF: 0.0165 AC: 998 AN: 60384

GnomAD4 genome AF: 0.0142 AC: 2158 AN: 152312 Hom.: 21 Cov.: 33 AF XY: 0.0136 AC XY: 1012 AN XY: 74482

African (AFR) AF: 0.00390 AC: 162 AN: 41566

American (AMR) AF: 0.0119 AC: 182 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00600 AC: 29 AN: 4832

European-Finnish (FIN) AF: 0.00659 AC: 70 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0232 AC: 1578 AN: 68024

Other (OTH) AF: 0.0156 AC: 33 AN: 2110

Alfa AF: 0.0177 Hom.: 13

Bravo AF: 0.0135

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	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	-0.72
CADD	Benign	3.5
DANN	Benign	0.87
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11573587; hg19: chr1-45293318; COSMIC: COSV100942217;