Genetic Variant NM_001184880.2:c.3018C>T (chrX-100296706-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001184880.2(PCDH19):c.3018C>T(p.Asp1006Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,209,196 control chromosomes in the GnomAD database, including 36 homozygotes. There are 841 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 21 hom., 388 hem., cov: 23)

Exomes 𝑓: 0.0016 ( 15 hom. 453 hem. )

Consequence

PCDH19
NM_001184880.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0540

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant X-100296706-G-A is Benign according to our data. Variant chrX-100296706-G-A is described in ClinVar as Benign. ClinVar VariationId is 138591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.054 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1449/111072) while in subpopulation AFR AF = 0.0429 (1305/30454). AF 95% confidence interval is 0.0409. There are 21 homozygotes in GnomAd4. There are 388 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 1449 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.3018C>T	p.Asp1006Asp	synonymous	Exon 6 of 6	NP_001171809.1	Q8TAB3-1
PCDH19	NM_001105243.2		c.2877C>T	p.Asp959Asp	synonymous	Exon 5 of 5	NP_001098713.1	Q8TAB3-2
PCDH19	NM_020766.3		c.2874C>T	p.Asp958Asp	synonymous	Exon 5 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.3018C>T	p.Asp1006Asp	synonymous	Exon 6 of 6	ENSP00000362125.4	Q8TAB3-1
PCDH19	ENST00000255531.8	TSL:1	c.2877C>T	p.Asp959Asp	synonymous	Exon 5 of 5	ENSP00000255531.7	Q8TAB3-2
PCDH19	ENST00000420881.6	TSL:1	c.2874C>T	p.Asp958Asp	synonymous	Exon 5 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1444

AN:

111018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0428

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00893

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000283

Gnomad SAS

AF:

0.000776

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.000434

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00433

AC:

786

AN:

181532

AF XY:

0.00311

show subpopulations

Gnomad AFR exome

AF:

0.0479

Gnomad AMR exome

AF:

0.00544

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000344

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00164

AC:

1804

AN:

1098124

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

453

AN XY:

363490

show subpopulations

African (AFR)

AF:

0.0470

AC:

1241

AN:

26398

American (AMR)

AF:

0.00608

AC:

214

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.000166

AC:

AN:

54142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00367

AC:

AN:

4091

European-Non Finnish (NFE)

AF:

0.000166

AC:

140

AN:

842077

Other (OTH)

AF:

0.00401

AC:

185

AN:

46086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0130

AC:

1449

AN:

111072

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

388

AN XY:

33300

show subpopulations

African (AFR)

AF:

0.0429

AC:

1305

AN:

30454

American (AMR)

AF:

0.00892

AC:

AN:

10534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.000284

AC:

AN:

3517

South Asian (SAS)

AF:

0.000778

AC:

AN:

2570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5905

Middle Eastern (MID)

AF:

0.00917

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000434

AC:

AN:

53036

Other (OTH)

AF:

0.0146

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

142

189

236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00465

Hom.:

Bravo

AF:

0.0154

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Developmental and epileptic encephalopathy, 9 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.87

(source)

DANN

Benign

0.71

PhyloP100

-0.054

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