rs61744561

Variant names:

• chrX-100402671-C-T
• rs61744561
• NM_001184880.2:c.2469G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001184880.2(PCDH19):​c.2469G>A​(p.Leu823Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,210,055 control chromosomes in the GnomAD database, including 19 homozygotes. There are 445 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (10 hom., 218 hem., cov: 23)
  • Exomes 𝑓: 0.00086 (9 hom. 227 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.66

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant X-100402671-C-T is Benign according to our data. Variant chrX-100402671-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.66 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00749 (839/112034) while in subpopulation AFR AF= 0.026 (802/30843). AF 95% confidence interval is 0.0245. There are 10 homozygotes in gnomad4. There are 218 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.2469G>A	p.Leu823Leu	synonymous_variant	Exon 3 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.2328G>A	p.Leu776Leu	synonymous_variant	Exon 2 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.2328G>A	p.Leu776Leu	synonymous_variant	Exon 2 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.2469G>A	p.Leu823Leu	synonymous_variant	Exon 3 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.2328G>A	p.Leu776Leu	synonymous_variant	Exon 2 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.2328G>A	p.Leu776Leu	synonymous_variant	Exon 2 of 5	1		ENSP00000400327.2
PCDH19	ENST00000636150.1	c.66-96G>A		intron_variant	Intron 1 of 2	5		ENSP00000490463.1

Frequencies

GnomAD3 genomes AF: 0.00747 AC: 836 AN: 111985 Hom.: 10 Cov.: 23 AF XY: 0.00632 AC XY: 216 AN XY: 34161

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00245

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: 0.0000940

Gnomad OTH AF: 0.00397

GnomAD3 exomes AF: 0.00218 AC: 396 AN: 181280 Hom.: 1 AF XY: 0.00129 AC XY: 87 AN XY: 67232

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000526

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000859 AC: 943 AN: 1098021 Hom.: 9 Cov.: 31 AF XY: 0.000625 AC XY: 227 AN XY: 363395

Gnomad4 AFR exome AF: 0.0293

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000924

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000273

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00749 AC: 839 AN: 112034 Hom.: 10 Cov.: 23 AF XY: 0.00637 AC XY: 218 AN XY: 34220

Gnomad4 AFR AF: 0.0260

Gnomad4 AMR AF: 0.00244

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000940

Gnomad4 OTH AF: 0.00392

Alfa AF: 0.00330 Hom.: 8

Bravo AF: 0.00853

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 09, 2023	- -

Developmental and epileptic encephalopathy, 9 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2025	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 17, 2022	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.1
DANN	Benign	0.72

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: rs61744561; hg19: chrX-99657669;