X-100408196-G-C

Variant names:

• chrX-100408196-G-C
• rs41300169
• NM_001184880.2:c.402C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001184880.2(PCDH19):​c.402C>G​(p.Ile134Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,142 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I134I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.89
• Publications: 6 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.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001184880.2
• 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=0.079910606).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184880.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	NM_001184880.2	MANE Select	c.402C>G	p.Ile134Met	missense	Exon 1 of 6	NP_001171809.1
	PCDH19	NM_001105243.2		c.402C>G	p.Ile134Met	missense	Exon 1 of 5	NP_001098713.1
	PCDH19	NM_020766.3		c.402C>G	p.Ile134Met	missense	Exon 1 of 5	NP_065817.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	ENST00000373034.8	TSL:1 MANE Select	c.402C>G	p.Ile134Met	missense	Exon 1 of 6	ENSP00000362125.4
	PCDH19	ENST00000255531.8	TSL:1	c.402C>G	p.Ile134Met	missense	Exon 1 of 5	ENSP00000255531.7
	PCDH19	ENST00000420881.6	TSL:1	c.402C>G	p.Ile134Met	missense	Exon 1 of 5	ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.00000551 AC: 1 AN: 181650 AF XY: 0.00

Gnomad AFR exome AF: 0.0000806

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098142 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363504

African (AFR) AF: 0.0000379 AC: 1 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40471

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842092

Other (OTH) AF: 0.00 AC: 0 AN: 46095

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 466

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.7
DANN	Benign	0.87
DEOGEN2	Benign	0.076	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.9	L
PhyloP100		-1.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.065	T
Sift4G	Uncertain	0.047	D
Polyphen		0.66	P
Vest4		0.25
MVP		0.38
MPC		2.1
ClinPred		0.12	T
GERP RS		-11
PromoterAI		-0.042	Neutral
Varity_R		0.57
gMVP		0.60
Mutation Taster		=57/43	polymorphism

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: rs41300169; hg19: chrX-99663194;