X-100402832-C-G

Variant names:

• chrX-100402832-C-G
• rs1036691760
• NM_001184880.2:c.2308G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001184880.2(PCDH19):​c.2308G>C​(p.Gly770Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46
• 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: Uncertain_significance. The variant received 2 ACMG points.

• 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=0.3461467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.2308G>C	p.Gly770Arg	missense_variant	Exon 3 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.2167G>C	p.Gly723Arg	missense_variant	Exon 2 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.2167G>C	p.Gly723Arg	missense_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.2308G>C	p.Gly770Arg	missense_variant	Exon 3 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.2167G>C	p.Gly723Arg	missense_variant	Exon 2 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.2167G>C	p.Gly723Arg	missense_variant	Exon 2 of 5	1		ENSP00000400327.2
PCDH19	ENST00000636150.1	c.66-257G>C		intron_variant	Intron 1 of 2	5		ENSP00000490463.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Uncertain:1

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. ClinVar contains an entry for this variant (Variation ID: 573321). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 770 of the PCDH19 protein (p.Gly770Arg). 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	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	.;T;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.34	.;N;.
PhyloP100		4.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.55	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.34	T;T;T
Sift4G	Uncertain	0.060	T;T;T
Polyphen		1.0, 1.0	.;D;D
Vest4		0.50
MutPred		0.25		.;Gain of solvent accessibility (P = 0.0971);.;
MVP		0.61
MPC		1.5
ClinPred		0.93	D
GERP RS		5.9
Varity_R		0.49
gMVP		0.48
Mutation Taster		=18/82	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: rs1036691760; hg19: chrX-99657830;