rs748581653

Variant names:

• chrX-100296851-C-G
• rs748581653
• NM_001184880.2:c.2873G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-100296851-C-G
• chrX-100296851-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001184880.2(PCDH19):​c.2873G>C​(p.Arg958Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,214 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. R958W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10
• 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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.2873G>C	p.Arg958Pro	missense_variant	Exon 6 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.2732G>C	p.Arg911Pro	missense_variant	Exon 5 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.2729G>C	p.Arg910Pro	missense_variant	Exon 5 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.2873G>C	p.Arg958Pro	missense_variant	Exon 6 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.2732G>C	p.Arg911Pro	missense_variant	Exon 5 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.2729G>C	p.Arg910Pro	missense_variant	Exon 5 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095214 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 360640

African (AFR) AF: 0.00 AC: 0 AN: 26333

American (AMR) AF: 0.00 AC: 0 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30190

South Asian (SAS) AF: 0.00 AC: 0 AN: 54069

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4051

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839490

Other (OTH) AF: 0.00 AC: 0 AN: 45976

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	.;T;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.6	.;L;.
PhyloP100		3.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.74	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.028	D;D;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.97, 0.92	.;D;P
Vest4		0.49
MutPred		0.31		.;Gain of sheet (P = 0.0049);.;
MVP		0.81
MPC		1.1
ClinPred		0.81	D
GERP RS		5.8
Varity_R		0.45
gMVP		0.67
Mutation Taster		=41/59	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: rs748581653; hg19: chrX-99551849;