1-44828037-G-T

Variant names:

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

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>A​(p.His622Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00339 in 1,614,192 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. H622Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (14 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• 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=0.0077517927).
• BP6: Variant 1-44828037-G-T is Benign according to our data. Variant chr1-44828037-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 252550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 357 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>A	p.His622Asn	missense	Exon 14 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.1864C>A	p.His622Asn	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>A	p.His622Asn	missense	Exon 14 of 22	ENSP00000361266.3
	PTCH2	ENST00000447098.7	TSL:1	c.1864C>A	p.His622Asn	missense	Exon 14 of 23	ENSP00000389703.2
	PTCH2	ENST00000881531.1		c.1813C>A	p.His605Asn	missense	Exon 14 of 22	ENSP00000551590.1

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00224 AC: 561 AN: 250818 AF XY: 0.00209

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00713

Gnomad NFE exome AF: 0.00326

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00350 AC: 5121 AN: 1461838 Hom.: 14 Cov.: 58 AF XY: 0.00336 AC XY: 2447 AN XY: 727226

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.000157 AC: 7 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: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00564 AC: 301 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00421 AC: 4679 AN: 1112004

Other (OTH) AF: 0.00182 AC: 110 AN: 60396

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.00234 AC XY: 174 AN XY: 74494

African (AFR) AF: 0.000962 AC: 40 AN: 41588

American (AMR) AF: 0.000327 AC: 5 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00687 AC: 73 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00351 AC: 239 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000120 Hom.: 78

Bravo AF: 0.00190

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00285 AC: 11

ExAC AF: 0.00189 AC: 230

EpiCase AF: 0.00273

EpiControl AF: 0.00332

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Gorlin syndrome (1)
-	-	1	PTCH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.0019
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.0078	T
MetaSVM	Uncertain	-0.044	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.22
Sift	Benign	0.36	T
Sift4G	Benign	0.34	T
Polyphen		0.030	B
Vest4		0.23
MVP		0.90
MPC		0.19
ClinPred		0.0095	T
GERP RS		4.3
Varity_R		0.15
gMVP		0.48
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: COSV64712437; COSMIC: COSV64712437;