X-100402718-T-G

Variant names:

• chrX-100402718-T-G
• rs111960928
• NM_001184880.2:c.2422A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001184880.2(PCDH19):​c.2422A>C​(p.Thr808Pro) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T808S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3342697).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.2422A>C	p.Thr808Pro	missense_variant	Exon 3 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.2281A>C	p.Thr761Pro	missense_variant	Exon 2 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.2281A>C	p.Thr761Pro	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.2422A>C	p.Thr808Pro	missense_variant	Exon 3 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.2281A>C	p.Thr761Pro	missense_variant	Exon 2 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.2281A>C	p.Thr761Pro	missense_variant	Exon 2 of 5	1		ENSP00000400327.2
PCDH19	ENST00000636150.1	c.66-143A>C		intron_variant	Intron 1 of 2	5		ENSP00000490463.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	.;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;D;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.34	.;N;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.030	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		1.0, 0.047	.;D;B
Vest4		0.43
MutPred		0.45		.;Loss of sheet (P = 0.007);.;
MVP		0.89
MPC		1.6
ClinPred		0.73	D
GERP RS		5.6
Varity_R		0.48
gMVP		0.48

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: rs111960928; hg19: chrX-99657716;