X-100296462-C-G

Variant names:

• chrX-100296462-C-G
• rs370078729
• NM_001184880.2:c.3262G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001184880.2(PCDH19):​c.3262G>C​(p.Ala1088Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,147 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1088T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.26
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: 2.5929 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Dravet syndrome, developmental and epileptic encephalopathy, 9, X-linked complex neurodevelopmental disorder.

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.3262G>C	p.Ala1088Pro	missense	Exon 6 of 6	NP_001171809.1
	PCDH19	NM_001105243.2		c.3121G>C	p.Ala1041Pro	missense	Exon 5 of 5	NP_001098713.1
	PCDH19	NM_020766.3		c.3118G>C	p.Ala1040Pro	missense	Exon 5 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.3262G>C	p.Ala1088Pro	missense	Exon 6 of 6	ENSP00000362125.4
	PCDH19	ENST00000255531.8	TSL:1	c.3121G>C	p.Ala1041Pro	missense	Exon 5 of 5	ENSP00000255531.7
	PCDH19	ENST00000420881.6	TSL:1	c.3118G>C	p.Ala1040Pro	missense	Exon 5 of 5	ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000551 AC: 1 AN: 181434 AF XY: 0.00

Gnomad AFR exome AF: 0.0000807

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098147 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363505

African (AFR) AF: 0.0000379 AC: 1 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35207

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40510

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842061

Other (OTH) AF: 0.00 AC: 0 AN: 46093

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.17
Sift	Uncertain	0.018	D
Sift4G	Benign	0.12	T
Polyphen		0.26	B
Vest4		0.53
MutPred		0.41		Gain of sheet (P = 0.0043)
MVP		0.66
MPC		0.65
ClinPred		0.14	T
GERP RS		4.1
Varity_R		0.26
gMVP		0.38
Mutation Taster		=82/18	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: rs370078729; hg19: chrX-99551460;