rs11573576

Variant names:

• chr1-44830974-G-A
• rs11573576
• NM_003738.5:c.687C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-44830974-G-A
• chr1-44830974-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003738.5(PTCH2):​c.687C>T​(p.Ala229Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,612,526 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (38 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (37 hom.)
• Consequence: PTCH2 NM_003738.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.06
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-44830974-G-A is Benign according to our data. Variant chr1-44830974-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.06 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1805/152298) while in subpopulation AFR AF = 0.0415 (1725/41554). AF 95% confidence interval is 0.0399. There are 38 homozygotes in GnomAd4. There are 900 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1805 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	NM_003738.5	MANE Select	c.687C>T	p.Ala229Ala	synonymous	Exon 6 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.687C>T	p.Ala229Ala	synonymous	Exon 6 of 23	NP_001159764.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH2	ENST00000372192.4	TSL:1 MANE Select	c.687C>T	p.Ala229Ala	synonymous	Exon 6 of 22	ENSP00000361266.3
	PTCH2	ENST00000447098.7	TSL:1	c.687C>T	p.Ala229Ala	synonymous	Exon 6 of 23	ENSP00000389703.2

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1804 AN: 152180 Hom.: 38 Cov.: 31

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

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: 0.000162

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00298 AC: 746 AN: 250696 AF XY: 0.00219

Gnomad AFR exome AF: 0.0402

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00118 AC: 1727 AN: 1460228 Hom.: 37 Cov.: 31 AF XY: 0.000989 AC XY: 718 AN XY: 726334

African (AFR) AF: 0.0408 AC: 1364 AN: 33440

American (AMR) AF: 0.00233 AC: 104 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00172 AC: 9 AN: 5226

European-Non Finnish (NFE) AF: 0.0000720 AC: 80 AN: 1111258

Other (OTH) AF: 0.00270 AC: 163 AN: 60278

GnomAD4 genome AF: 0.0119 AC: 1805 AN: 152298 Hom.: 38 Cov.: 31 AF XY: 0.0121 AC XY: 900 AN XY: 74458

African (AFR) AF: 0.0415 AC: 1725 AN: 41554

American (AMR) AF: 0.00418 AC: 64 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00506 Hom.: 8

Bravo AF: 0.0136

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (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	-0.42
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		1.1
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: rs11573576; hg19: chr1-45296646;