rs16983426

chrX-100296706-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001184880.2(PCDH19):c.3018C>T(p.Asp1006=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0540

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 138591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100296706-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.3018C>T	p.Asp1006=	synonymous_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.2877C>T	p.Asp959=	synonymous_variant	5/5
PCDH19	NM_020766.3	c.2874C>T	p.Asp958=	synonymous_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.3018C>T	p.Asp1006=	synonymous_variant	6/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.2877C>T	p.Asp959=	synonymous_variant	5/5	1		P5
PCDH19	ENST00000420881.6	c.2874C>T	p.Asp958=	synonymous_variant	5/5	1		A1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1444 AN: 111018 Hom.: 21 Cov.: 23 AF XY: 0.0116 AC XY: 387 AN XY: 33236

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

GnomAD3 exomes AF: 0.00433 AC: 786 AN: 181532 Hom.: 8 AF XY: 0.00311 AC XY: 210 AN XY: 67492

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 SAS exome AF: 0.000210

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.: 15 Cov.: 31 AF XY: 0.00125 AC XY: 453 AN XY: 363490

Gnomad4 AFR exome AF: 0.0470

Gnomad4 AMR exome AF: 0.00608

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000166

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.0130 AC: 1449 AN: 111072 Hom.: 21 Cov.: 23 AF XY: 0.0117 AC XY: 388 AN XY: 33300

Gnomad4 AFR AF: 0.0429

Gnomad4 AMR AF: 0.00892

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000284

Gnomad4 SAS AF: 0.000778

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000434

Gnomad4 OTH AF: 0.0146

Alfa AF: 0.00465 Hom.: 38

Bravo AF: 0.0154

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 27, 2017

- -

Developmental and epileptic encephalopathy, 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	0.87
Dann	Benign	0.71

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

Other links and lift over

dbSNP: rs16983426; hg19: chrX-99551704; COSMIC: COSV55262261; COSMIC: COSV55262261;