rs200142964

Variant names:

• chrX-100407948-G-A
• NM_001184880.2:c.650C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-100407948-G-A
• chrX-100407948-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001184880.2(PCDH19):​c.650C>T​(p.Pro217Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 24)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.13

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Cadherin 2 (size 108) in uniprot entity PCD19_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001184880.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.650C>T	p.Pro217Leu	missense_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.650C>T	p.Pro217Leu	missense_variant	Exon 1 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.650C>T	p.Pro217Leu	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.650C>T	p.Pro217Leu	missense_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.650C>T	p.Pro217Leu	missense_variant	Exon 1 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.650C>T	p.Pro217Leu	missense_variant	Exon 1 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.8	M;M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.72
MutPred		0.53		Loss of disorder (P = 0.0283);Loss of disorder (P = 0.0283);Loss of disorder (P = 0.0283);
MVP		0.61
MPC		2.4
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.66
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-99662946;