rs1338518342

Variant names:

• chrX-100407809-G-A
• rs1338518342
• NM_001184880.2:c.789C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001184880.2(PCDH19):​c.789C>T​(p.Ser263Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,211,171 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.90
• Publications: 0 publications found

Genes affected

PCDH19 (HGNC:14270): (protocadherin 19) The protein encoded by this gene is a member of the delta-2 protocadherin subclass of the cadherin superfamily. The encoded protein is thought to be a calcium-dependent cell-adhesion protein that is primarily expressed in the brain. Mutations in this gene on human chromosome X are associated with sporadic infantile epileptic encephalopathy and to a female-restricted form of epilepsy (EFMR; also known as PCDH19RE). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

PCDH19 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 9

  Inheritance: XL, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-100407809-G-A is Benign according to our data. Variant chrX-100407809-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 465309.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.9 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184880.2. 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
	PCDH19	NM_001184880.2	MANE Select	c.789C>T	p.Ser263Ser	synonymous	Exon 1 of 6	NP_001171809.1
	PCDH19	NM_001105243.2		c.789C>T	p.Ser263Ser	synonymous	Exon 1 of 5	NP_001098713.1
	PCDH19	NM_020766.3		c.789C>T	p.Ser263Ser	synonymous	Exon 1 of 5	NP_065817.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	ENST00000373034.8	TSL:1 MANE Select	c.789C>T	p.Ser263Ser	synonymous	Exon 1 of 6	ENSP00000362125.4
	PCDH19	ENST00000255531.8	TSL:1	c.789C>T	p.Ser263Ser	synonymous	Exon 1 of 5	ENSP00000255531.7
	PCDH19	ENST00000420881.6	TSL:1	c.789C>T	p.Ser263Ser	synonymous	Exon 1 of 5	ENSP00000400327.2

Frequencies

GnomAD3 genomes AF: 0.00000885 AC: 1 AN: 113046 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000187

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1098125 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 1 AN XY: 363481

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 842059

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome AF: 0.00000885 AC: 1 AN: 113046 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 35184

African (AFR) AF: 0.00 AC: 0 AN: 31135

American (AMR) AF: 0.00 AC: 0 AN: 10810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53380

Other (OTH) AF: 0.00 AC: 0 AN: 1532

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.0
DANN	Benign	0.90
PhyloP100		-2.9

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: rs1338518342; hg19: chrX-99662807; COSMIC: COSV55274263; COSMIC: COSV55274263;