rs779136255

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_ModerateBS2

The NM_001184880.2(PCDH19):c.2263_2288+1dupGAGAAAGTGAGCCTAAGGGGAAAGAGG variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000317 in 1,200,396 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000033 ( 0 hom. 10 hem. )

Consequence

PCDH19
NM_001184880.2 splice_donor, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.91

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.040905137 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.9, offset of 7, new splice context is: aaaGTgagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BS2

High AC in GnomAdExome4 at 36 AD,XL,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2 link	c.2263_2288+1dupGAGAAAGTGAGCCTAAGGGGAAAGAGG	splice_donor_variant, intron_variant	Intron 2 of 5	ENST00000373034.8	NP_001171809.1	Q8TAB3-1
PCDH19	NM_001105243.2 link	c.2148-698_2148-672dupGAGAAAGTGAGCCTAAGGGGAAAGAGG	intron_variant	Intron 1 of 4		NP_001098713.1	Q8TAB3-2B3KU71
PCDH19	NM_020766.3 link	c.2148-698_2148-672dupGAGAAAGTGAGCCTAAGGGGAAAGAGG	intron_variant	Intron 1 of 4		NP_065817.2	Q8TAB3-3B3KU71

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCDH19	ENST00000373034.8 link	c.2288+1_2288+2insGAGAAAGTGAGCCTAAGGGGAAAGAGG	splice_donor_variant, intron_variant	Intron 2 of 5	1	NM_001184880.2	ENSP00000362125.4	Q8TAB3-1
PCDH19	ENST00000255531.8 link	c.2148-672_2148-671insGAGAAAGTGAGCCTAAGGGGAAAGAGG	intron_variant	Intron 1 of 4	1		ENSP00000255531.7	Q8TAB3-2
PCDH19	ENST00000420881.6 link	c.2148-672_2148-671insGAGAAAGTGAGCCTAAGGGGAAAGAGG	intron_variant	Intron 1 of 4	1		ENSP00000400327.2	Q8TAB3-3
PCDH19	ENST00000636150.1 link	c.66-948_66-947insGAGAAAGTGAGCCTAAGGGGAAAGAGG	intron_variant	Intron 1 of 2	5		ENSP00000490463.1	A0A1B0GVC8

Frequencies

GnomAD3 genomes

AF:

0.0000184

AC:

AN:

108773

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000381

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000582

AC:

AN:

171722

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000133

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000330

AC:

AN:

1091623

Hom.:

Cov.:

AF XY:

0.0000278

AC XY:

AN XY:

359203

show subpopulations

African (AFR)

AF:

0.0000382

AC:

AN:

26144

American (AMR)

AF:

0.00

AC:

AN:

34656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19258

East Asian (EAS)

AF:

0.00

AC:

AN:

29775

South Asian (SAS)

AF:

0.00

AC:

AN:

53385

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3338

European-Non Finnish (NFE)

AF:

0.0000393

AC:

AN:

839722

Other (OTH)

AF:

0.0000437

AC:

AN:

45783

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

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:

0.0000184

AC:

AN:

108773

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

31743

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29695

American (AMR)

AF:

0.00

AC:

AN:

10022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2629

East Asian (EAS)

AF:

0.00

AC:

AN:

3435

South Asian (SAS)

AF:

0.00

AC:

AN:

2516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

226

European-Non Finnish (NFE)

AF:

0.0000381

AC:

AN:

52475

Other (OTH)

AF:

0.00

AC:

AN:

1461

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 9

Uncertain:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.2262_2288dup, results in the insertion of 9 amino acid(s) of the PCDH19 protein (p.Glu755_Arg763dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779136255, gnomAD 0.001%). This variant has been observed in individual(s) with clinical features of PCDH19-related conditions (internal data). This variant is also known as c.2263_2288+1dup. ClinVar contains an entry for this variant (Variation ID: 533850). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.9

Mutation Taster

=57/43

polymorphism

(source)

Splicing

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