NM_001184880.2:c.2308G>A

Variant names:

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

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>A​(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.34880465).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

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	29
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		0.94	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)		0.10		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;