X-100406927-G-T

Variant names:

• chrX-100406927-G-T
• rs267606933
• NM_001184880.2:c.1671C>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001184880.2(PCDH19):​c.1671C>A​(p.Asn557Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N557S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0890
• Publications: 0 publications found

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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS1: Transcript NM_001184880.2 (PCDH19) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 11022
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001184880.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: 2.5929 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Dravet syndrome, developmental and epileptic encephalopathy, 9, X-linked complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant X-100406927-G-T is Pathogenic according to our data. Variant chrX-100406927-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2780476.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.1671C>A	p.Asn557Lys	missense_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.1671C>A	p.Asn557Lys	missense_variant	Exon 1 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.1671C>A	p.Asn557Lys	missense_variant	Exon 1 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.1671C>A	p.Asn557Lys	missense_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.1671C>A	p.Asn557Lys	missense_variant	Exon 1 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.1671C>A	p.Asn557Lys	missense_variant	Exon 1 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Pathogenic:1

Aug 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn557 amino acid residue in PCDH19. Other variant(s) that disrupt this residue have been observed in individuals with PCDH19-related conditions (PMID: 18469813; Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects PCDH19 function (PMID: 34082468). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCDH19 protein function. This missense change has been observed in individuals with clinical features of epilepsy and autism spectrum disorder (PMID: 18469813; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 557 of the PCDH19 protein (p.Asn557Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D;.
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	5.0	H;H;H
PhyloP100		-0.089
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.95
MutPred		0.90		Gain of methylation at N557 (P = 0.0042);Gain of methylation at N557 (P = 0.0042);Gain of methylation at N557 (P = 0.0042);
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		-1.1
PromoterAI		-0.041	Neutral
Varity_R		0.98
gMVP		0.99
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs267606933; hg19: chrX-99661925;