rs11573586

Variant names:

• chr1-44828037-G-A
• rs11573586
• NM_003738.5:c.1864C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-44828037-G-A
• chr1-44828037-G-C
• chr1-44828037-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003738.5(PTCH2):​c.1864C>T​(p.His622Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0118 in 1,614,188 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H622N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0089 (6 hom., cov: 33)
  • Exomes 𝑓: 0.012 (120 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.05
• Publications: 19 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067539215).
• BP6: Variant 1-44828037-G-A is Benign according to our data. Variant chr1-44828037-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1355 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.1864C>T	p.His622Tyr	missense	Exon 14 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.1864C>T	p.His622Tyr	missense	Exon 14 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.1864C>T	p.His622Tyr	missense	Exon 14 of 22	ENSP00000361266.3
	PTCH2	ENST00000447098.7	TSL:1	c.1864C>T	p.His622Tyr	missense	Exon 14 of 23	ENSP00000389703.2
	PTCH2	ENST00000881531.1		c.1813C>T	p.His605Tyr	missense	Exon 14 of 22	ENSP00000551590.1

Frequencies

GnomAD3 genomes AF: 0.00889 AC: 1354 AN: 152236 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00947 AC: 2376 AN: 250818 AF XY: 0.00950

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.00832

GnomAD4 exome AF: 0.0121 AC: 17708 AN: 1461834 Hom.: 120 Cov.: 58 AF XY: 0.0119 AC XY: 8666 AN XY: 727222

African (AFR) AF: 0.00182 AC: 61 AN: 33480

American (AMR) AF: 0.00226 AC: 101 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 120 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00540 AC: 466 AN: 86256

European-Finnish (FIN) AF: 0.0125 AC: 669 AN: 53376

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

European-Non Finnish (NFE) AF: 0.0141 AC: 15724 AN: 1111998

Other (OTH) AF: 0.00907 AC: 548 AN: 60396

GnomAD4 genome AF: 0.00889 AC: 1355 AN: 152354 Hom.: 6 Cov.: 33 AF XY: 0.00863 AC XY: 643 AN XY: 74494

African (AFR) AF: 0.00207 AC: 86 AN: 41588

American (AMR) AF: 0.00464 AC: 71 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4832

European-Finnish (FIN) AF: 0.0134 AC: 142 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0147 AC: 1001 AN: 68030

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.0124 Hom.: 78

Bravo AF: 0.00757

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0138 AC: 119

ExAC AF: 0.0101 AC: 1221

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0126

EpiControl AF: 0.0102

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Basal cell carcinoma, susceptibility to, 1 (1)
-	-	1	Basal cell nevus syndrome 1 (1)
-	-	1	Gorlin syndrome (1)
-	-	1	PTCH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.018
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0068	T
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Benign	0.60	N
PhyloP100		5.0
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.23
Sift	Benign	0.036	D
Sift4G	Uncertain	0.053	T
Polyphen		0.0030	B
Vest4		0.25
MPC		0.20
ClinPred		0.010	T
GERP RS		4.3
Varity_R		0.15
gMVP		0.52
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11573586; hg19: chr1-45293709; COSMIC: COSV64713147;