rs139624405

Variant names:

• chr1-44829624-C-T
• rs139624405
• NM_003738.5:c.1073G>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.1073G>A​(p.Arg358His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 1,614,206 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts 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. R358C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0066 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (60 hom.)
• Consequence: PTCH2 NM_003738.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.08
• Publications: 13 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=0.010429025).
• BP6: Variant 1-44829624-C-T is Benign according to our data. Variant chr1-44829624-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1006 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.1073G>A	p.Arg358His	missense	Exon 8 of 22	NP_003729.3
	PTCH2	NM_001166292.2		c.1073G>A	p.Arg358His	missense	Exon 8 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.1073G>A	p.Arg358His	missense	Exon 8 of 22	ENSP00000361266.3
	PTCH2	ENST00000447098.7	TSL:1	c.1073G>A	p.Arg358His	missense	Exon 8 of 23	ENSP00000389703.2

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 1006 AN: 152214 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00891

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00674 AC: 1694 AN: 251364 AF XY: 0.00647

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.00955

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00747 AC: 10924 AN: 1461874 Hom.: 60 Cov.: 33 AF XY: 0.00724 AC XY: 5267 AN XY: 727242

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00219 AC: 98 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000939 AC: 81 AN: 86258

European-Finnish (FIN) AF: 0.0188 AC: 1003 AN: 53400

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00841 AC: 9352 AN: 1112012

Other (OTH) AF: 0.00538 AC: 325 AN: 60396

GnomAD4 genome AF: 0.00660 AC: 1006 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00698 AC XY: 520 AN XY: 74482

African (AFR) AF: 0.00183 AC: 76 AN: 41580

American (AMR) AF: 0.00621 AC: 95 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

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

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.0197 AC: 209 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00891 AC: 606 AN: 68026

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00735 Hom.: 14

Bravo AF: 0.00515

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00721 AC: 875

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00735

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	Gorlin syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.2	L
PhyloP100		3.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.55
Sift	Benign	0.030	D
Sift4G	Benign	0.081	T
Polyphen		0.96	D
Vest4		0.21
MVP		0.98
MPC		0.54
ClinPred		0.033	T
GERP RS		5.0
Varity_R		0.084
gMVP		0.29
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: rs139624405; hg19: chr1-45295296; COSMIC: COSV106109273;