X-100408456-C-T

Variant names:

• chrX-100408456-C-T
• rs132630326
• NM_001184880.2:c.142G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001184880.2(PCDH19):​c.142G>A​(p.Glu48Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65
• Publications: 4 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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1459035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.142G>A	p.Glu48Lys	missense_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.142G>A	p.Glu48Lys	missense_variant	Exon 1 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.142G>A	p.Glu48Lys	missense_variant	Exon 1 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.142G>A	p.Glu48Lys	missense_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.142G>A	p.Glu48Lys	missense_variant	Exon 1 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.142G>A	p.Glu48Lys	missense_variant	Exon 1 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00 AC: 0 AN: 167729 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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 Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.032	.;T;.
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N;N;N
PhyloP100		3.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Benign	0.054
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.79	T;T;T
Polyphen		0.010, 0.0010	.;B;B
Vest4		0.13
MutPred		0.59		Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);
MVP		0.32
MPC		1.3
ClinPred		0.50	D
GERP RS		5.7
PromoterAI		-0.055	Neutral
Varity_R		0.29
gMVP		0.64
Mutation Taster		=70/30	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: rs132630326; hg19: chrX-99663454;