Variant X-100296312-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001184880.2(PCDH19):c.3412C>G(p.Pro1138Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000579 in 1,209,129 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 2 hem. )

Consequence

PCDH19
NM_001184880.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.33

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29782397).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PCDH19	NM_001184880.2 linkuse as main transcript	c.3412C>G	p.Pro1138Ala	missense_variant	6/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2 linkuse as main transcript	c.3271C>G	p.Pro1091Ala	missense_variant	5/5		NP_001098713.1
PCDH19	NM_020766.3 linkuse as main transcript	c.3268C>G	p.Pro1090Ala	missense_variant	5/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8 linkuse as main transcript	c.3412C>G	p.Pro1138Ala	missense_variant	6/6	1	NM_001184880.2	ENSP00000362125	A1	Q8TAB3-1
PCDH19	ENST00000255531.8 linkuse as main transcript	c.3271C>G	p.Pro1091Ala	missense_variant	5/5	1		ENSP00000255531	P5	Q8TAB3-2
PCDH19	ENST00000420881.6 linkuse as main transcript	c.3268C>G	p.Pro1090Ala	missense_variant	5/5	1		ENSP00000400327	A1	Q8TAB3-3
PCDH19	ENST00000464981.1 linkuse as main transcript			upstream_gene_variant		3		ENSP00000479805

Frequencies

GnomAD3 genomes

AF:

0.0000358

AC:

AN:

111788

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

33970

show subpopulations

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:

0.0000753

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000551

AC:

AN:

181603

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67533

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1097341

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

362715

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000357

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000358

AC:

AN:

111788

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

33970

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000753

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000209

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.056

.;T;.

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.97

.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.011

D;D;D

Sift4G

Benign

0.45

T;T;T

Polyphen

0.73, 0.72

.;P;P

Vest4

0.47

MutPred

0.30

.;Loss of loop (P = 0.0288);.;

MVP

0.76

MPC

0.76

ClinPred

0.34

GERP RS

5.5

Varity_R

0.30

gMVP

0.27

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over