NM_001184880.2:c.1618C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001184880.2(PCDH19):c.1618C>T(p.Leu540Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,210,262 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 241 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L540L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 19 hem., cov: 24)

Exomes 𝑓: 0.00036 ( 0 hom. 222 hem. )

Consequence

PCDH19
NM_001184880.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.313

Publications

1 publications found

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 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

PCDH19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_001184880.2

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=0.01000607).

BP6

Variant X-100406980-G-A is Benign according to our data. Variant chrX-100406980-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 206334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000232 (26/112053) while in subpopulation SAS AF = 0.00986 (26/2638). AF 95% confidence interval is 0.00691. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAd4 at 26 AD,XL,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2 link	c.1618C>T	p.Leu540Phe	missense_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1	Q8TAB3-1
PCDH19	NM_001105243.2 link	c.1618C>T	p.Leu540Phe	missense_variant	Exon 1 of 5		NP_001098713.1	Q8TAB3-2B3KU71
PCDH19	NM_020766.3 link	c.1618C>T	p.Leu540Phe	missense_variant	Exon 1 of 5		NP_065817.2	Q8TAB3-3B3KU71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCDH19	ENST00000373034.8 link	c.1618C>T	p.Leu540Phe	missense_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4	Q8TAB3-1
PCDH19	ENST00000255531.8 link	c.1618C>T	p.Leu540Phe	missense_variant	Exon 1 of 5	1		ENSP00000255531.7	Q8TAB3-2
PCDH19	ENST00000420881.6 link	c.1618C>T	p.Leu540Phe	missense_variant	Exon 1 of 5	1		ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.000241

AC:

AN:

111998

Hom.:

Cov.:

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:

0.0102

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000666

AC:

121

AN:

181793

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000630

Gnomad NFE exome

AF:

0.0000368

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.000361

AC:

397

AN:

1098209

Hom.:

Cov.:

AF XY:

0.000611

AC XY:

222

AN XY:

363567

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.0000284

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00615

AC:

333

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40502

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000499

AC:

AN:

842124

Other (OTH)

AF:

0.000434

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000232

AC:

AN:

112053

Hom.:

Cov.:

AF XY:

0.000556

AC XY:

AN XY:

34203

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30887

American (AMR)

AF:

0.00

AC:

AN:

10668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3527

South Asian (SAS)

AF:

0.00986

AC:

AN:

2638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6059

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53197

Other (OTH)

AF:

0.00

AC:

AN:

1521

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000341

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000990

AC:

120

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 9

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.89

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

.;T;.

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

N;N;N

PhyloP100

0.31

PrimateAI

Uncertain

0.50

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.050

Sift

Benign

0.10

T;T;T

Sift4G

Uncertain

0.021

D;D;D

Polyphen

0.25, 0.71

.;B;P

Vest4

0.19

MutPred

0.39

Loss of ubiquitination at K536 (P = 0.0578);Loss of ubiquitination at K536 (P = 0.0578);Loss of ubiquitination at K536 (P = 0.0578);

MVP

0.22

MPC

0.65

ClinPred

0.026

GERP RS

1.6

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.094

gMVP

0.23

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over