rs796052790

Variant names:

• chrX-100408374-T-C
• rs796052790
• NM_001184880.2:c.224A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

The NM_001184880.2(PCDH19):​c.224A>G​(p.Asn75Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,207,697 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 B:1
• Conservation: PhyloP100: 2.62
• Publications: 1 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001184880.2
• 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 developmental and epileptic encephalopathy, 9, X-linked complex neurodevelopmental disorder, Dravet syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21575347).
• BS2: High Hemizygotes in GnomAd4 at 2 XL,Unknown,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	NM_001184880.2	MANE Select	c.224A>G	p.Asn75Ser	missense	Exon 1 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.224A>G	p.Asn75Ser	missense	Exon 1 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.224A>G	p.Asn75Ser	missense	Exon 1 of 5	NP_065817.2	Q8TAB3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	ENST00000373034.8	TSL:1 MANE Select	c.224A>G	p.Asn75Ser	missense	Exon 1 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.224A>G	p.Asn75Ser	missense	Exon 1 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.224A>G	p.Asn75Ser	missense	Exon 1 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.0000360 AC: 4 AN: 110993 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000757

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000556 AC: 1 AN: 179728 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

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: 0.00000182 AC: 2 AN: 1096704 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1 AN XY: 362332

African (AFR) AF: 0.00 AC: 0 AN: 26390

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39409

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841776

Other (OTH) AF: 0.00 AC: 0 AN: 46079

GnomAD4 genome AF: 0.0000360 AC: 4 AN: 110993 Hom.: 0 Cov.: 24 AF XY: 0.0000602 AC XY: 2 AN XY: 33213

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30568

American (AMR) AF: 0.00 AC: 0 AN: 10604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3463

South Asian (SAS) AF: 0.00 AC: 0 AN: 2561

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5935

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000757 AC: 4 AN: 52816

Other (OTH) AF: 0.00 AC: 0 AN: 1492

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Developmental and epileptic encephalopathy, 9 (3)
-	-	1	Neurodevelopmental disorder with epilepsy (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.10
Sift	Benign	0.14	T
Sift4G	Benign	0.28	T
Polyphen		0.0070	B
Vest4		0.22
MutPred		0.65		Gain of disorder (P = 0.034)
MVP		0.56
MPC		0.96
ClinPred		0.13	T
GERP RS		5.7
PromoterAI		-0.029	Neutral
Varity_R		0.37
gMVP		0.22
Mutation Taster		=93/7	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: rs796052790; hg19: chrX-99663372;