rs748581653

Positions:

• chrX-100296851-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001184880.2(PCDH19):​c.2873G>A​(p.Arg958Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,206,546 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 82 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R958W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.00017 (0 hom. 77 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.10

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035001665).
• BP6: Variant X-100296851-C-T is Benign according to our data. Variant chrX-100296851-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 206362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100296851-C-T is described in Lovd as [Benign]. Variant chrX-100296851-C-T is described in Lovd as [Likely_benign]. Variant chrX-100296851-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000988 (11/111336) while in subpopulation SAS AF= 0.00195 (5/2561). AF 95% confidence interval is 0.000769. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.2873G>A	p.Arg958Gln	missense_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.2732G>A	p.Arg911Gln	missense_variant	5/5
PCDH19	NM_020766.3	c.2729G>A	p.Arg910Gln	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.2873G>A	p.Arg958Gln	missense_variant	6/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.2732G>A	p.Arg911Gln	missense_variant	5/5	1		P5
PCDH19	ENST00000420881.6	c.2729G>A	p.Arg910Gln	missense_variant	5/5	1		A1

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111282 Hom.: 1 Cov.: 22 AF XY: 0.000149 AC XY: 5 AN XY: 33480

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00195

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.0000755

Gnomad OTH AF: 0.000667

GnomAD3 exomes AF: 0.000194 AC: 35 AN: 180554 Hom.: 0 AF XY: 0.000284 AC XY: 19 AN XY: 66824

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 SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000497

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000174 AC: 191 AN: 1095210 Hom.: 0 Cov.: 29 AF XY: 0.000214 AC XY: 77 AN XY: 360638

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000762

Gnomad4 OTH exome AF: 0.000239

GnomAD4 genome AF: 0.0000988 AC: 11 AN: 111336 Hom.: 0 Cov.: 22 AF XY: 0.000149 AC XY: 5 AN XY: 33544

Gnomad4 AFR AF: 0.0000326

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00195

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000755

Gnomad4 OTH AF: 0.000658

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.000289 AC: 35

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Sep 24, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

This alteration is classified as likely 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. -

PCDH19-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

PCDH19: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.12	N;N;N
REVEL	Benign	0.040
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.12, 0.14	.;B;B
Vest4		0.24
MutPred		0.33		.;Gain of sheet (P = 0.0049);.;
MVP		0.59
MPC		0.59
ClinPred		0.023	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.16

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: rs748581653; hg19: chrX-99551849; COSMIC: COSV55269911; COSMIC: COSV55269911;