Genetic Variant PCDH19:p.Asn932Asn (chrX-100341955-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001184880.2(PCDH19):c.2796C>T(p.Asn932Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,207,622 control chromosomes in the GnomAD database, including 6 homozygotes. There are 1,317 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., 76 hem., cov: 23)

Exomes 𝑓: 0.0034 ( 5 hom. 1241 hem. )

Consequence

PCDH19
NM_001184880.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: -0.133

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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant X-100341955-G-A is Benign according to our data. Variant chrX-100341955-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138601.

BP7

Synonymous conserved (PhyloP=-0.133 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00237 (265/111965) while in subpopulation SAS AF = 0.00453 (12/2647). AF 95% confidence interval is 0.00319. There are 1 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 265 AD,XL,Unknown gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCDH19	NM_001184880.2	MANE Select	c.2796C>T	p.Asn932Asn	synonymous	Exon 5 of 6	NP_001171809.1	Q8TAB3-1
PCDH19	NM_001105243.2		c.2655C>T	p.Asn885Asn	synonymous	Exon 4 of 5	NP_001098713.1	Q8TAB3-2
PCDH19	NM_020766.3		c.2652C>T	p.Asn884Asn	synonymous	Exon 4 of 5	NP_065817.2	Q8TAB3-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCDH19	ENST00000373034.8	TSL:1 MANE Select	c.2796C>T	p.Asn932Asn	synonymous	Exon 5 of 6	ENSP00000362125.4	Q8TAB3-1
PCDH19	ENST00000255531.8	TSL:1	c.2655C>T	p.Asn885Asn	synonymous	Exon 4 of 5	ENSP00000255531.7	Q8TAB3-2
PCDH19	ENST00000420881.6	TSL:1	c.2652C>T	p.Asn884Asn	synonymous	Exon 4 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.00236

AC:

264

AN:

111915

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00133

Gnomad ASJ

AF:

0.00415

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.000328

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.00361

Gnomad OTH

AF:

0.00199

GnomAD2 exomes

AF:

0.00274

AC:

498

AN:

181689

AF XY:

0.00289

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00388

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000628

Gnomad NFE exome

AF:

0.00354

Gnomad OTH exome

AF:

0.00516

GnomAD4 exome

AF:

0.00335

AC:

3672

AN:

1095657

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

1241

AN XY:

361097

show subpopulations

African (AFR)

AF:

0.000873

AC:

AN:

26347

American (AMR)

AF:

0.00236

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

19364

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.00361

AC:

195

AN:

54082

European-Finnish (FIN)

AF:

0.000148

AC:

AN:

40521

Middle Eastern (MID)

AF:

0.00728

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.00370

AC:

3106

AN:

839805

Other (OTH)

AF:

0.00352

AC:

162

AN:

46012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

126

252

379

505

631

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.00237

AC:

265

AN:

111965

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

AN XY:

34159

show subpopulations

African (AFR)

AF:

0.000972

AC:

AN:

30879

American (AMR)

AF:

0.00133

AC:

AN:

10545

Ashkenazi Jewish (ASJ)

AF:

0.00415

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.00453

AC:

AN:

2647

European-Finnish (FIN)

AF:

0.000328

AC:

AN:

6092

Middle Eastern (MID)

AF:

0.00913

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00361

AC:

192

AN:

53171

Other (OTH)

AF:

0.00131

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.00323

Hom.:

Bravo

AF:

0.00241

EpiCase

AF:

0.00540

EpiControl

AF:

0.00587

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Developmental and epileptic encephalopathy, 9 (2)

not provided (2)

Inborn genetic diseases (1)

PCDH19-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.46

(source)

DANN

Benign

0.68

PhyloP100

-0.13

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over