NM_001184880.2:c.402C>G

Variant names:

• chrX-100408196-G-C
• rs41300169
• NM_001184880.2:c.402C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001184880.2(PCDH19):​c.402C>G​(p.Ile134Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,142 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I134I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.89
• Publications: 6 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.079910606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.402C>G	p.Ile134Met	missense_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.402C>G	p.Ile134Met	missense_variant	Exon 1 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.402C>G	p.Ile134Met	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.402C>G	p.Ile134Met	missense_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.402C>G	p.Ile134Met	missense_variant	Exon 1 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.402C>G	p.Ile134Met	missense_variant	Exon 1 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.00000551 AC: 1 AN: 181650 AF XY: 0.00

Gnomad AFR exome AF: 0.0000806

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098142 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363504

African (AFR) AF: 0.0000379 AC: 1 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40471

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842092

Other (OTH) AF: 0.00 AC: 0 AN: 46095

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 466

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Uncertain:1

Aug 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 134 of the PCDH19 protein (p.Ile134Met). This variant is present in population databases (no rsID available, gnomAD 0.008%). 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 not expected to disrupt PCDH19 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.7
DANN	Benign	0.87
DEOGEN2	Benign	0.076	.;T;.
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.9	L;L;L
PhyloP100		-1.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.065	T;D;T
Sift4G	Uncertain	0.047	D;T;D
Polyphen		0.66, 0.85	.;P;P
Vest4		0.25
MVP		0.38
MPC		2.1
ClinPred		0.12	T
GERP RS		-11
PromoterAI		-0.042	Neutral
Varity_R		0.57
gMVP		0.60
Mutation Taster		=57/43	polymorphism

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: rs41300169; hg19: chrX-99663194;