rs3764758

Variant names:

• chrX-100296786-G-A
• rs3764758
• NM_001184880.2:c.2938C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001184880.2(PCDH19):​c.2938C>T​(p.Arg980Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00131 in 1,209,314 control chromosomes in the GnomAD database, including 21 homozygotes. There are 488 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R980H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., 79 hem., cov: 22)
  • Exomes 𝑓: 0.0012 (18 hom. 409 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.52
• Publications: 7 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: Benign. The variant received -19 ACMG points.

• 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=0.010465592).
• BP6: Variant X-100296786-G-A is Benign according to our data. Variant chrX-100296786-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

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.2938C>T	p.Arg980Cys	missense	Exon 6 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.2797C>T	p.Arg933Cys	missense	Exon 5 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.2794C>T	p.Arg932Cys	missense	Exon 5 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.2938C>T	p.Arg980Cys	missense	Exon 6 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.2797C>T	p.Arg933Cys	missense	Exon 5 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.2794C>T	p.Arg932Cys	missense	Exon 5 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 228 AN: 111790 Hom.: 3 Cov.: 22

Gnomad AFR AF: 0.000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0563

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.000665

GnomAD2 exomes AF: 0.00479 AC: 870 AN: 181478 AF XY: 0.00405

Gnomad AFR exome AF: 0.000645

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0609

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00124 AC: 1359 AN: 1097470 Hom.: 18 Cov.: 30 AF XY: 0.00113 AC XY: 409 AN XY: 362840

African (AFR) AF: 0.000303 AC: 8 AN: 26387

American (AMR) AF: 0.000114 AC: 4 AN: 35207

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

East Asian (EAS) AF: 0.0377 AC: 1139 AN: 30200

South Asian (SAS) AF: 0.00139 AC: 75 AN: 54128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4098

European-Non Finnish (NFE) AF: 0.0000357 AC: 30 AN: 841474

Other (OTH) AF: 0.00224 AC: 103 AN: 46060

GnomAD4 genome AF: 0.00204 AC: 228 AN: 111844 Hom.: 3 Cov.: 22 AF XY: 0.00232 AC XY: 79 AN XY: 34010

African (AFR) AF: 0.000487 AC: 15 AN: 30792

American (AMR) AF: 0.000188 AC: 2 AN: 10612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.0565 AC: 199 AN: 3524

South Asian (SAS) AF: 0.00270 AC: 7 AN: 2588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6083

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000752 AC: 4 AN: 53167

Other (OTH) AF: 0.000657 AC: 1 AN: 1522

Alfa AF: 0.00184 Hom.: 29

Bravo AF: 0.00244

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000838 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00452 AC: 547

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy, 9 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.9	M
PhyloP100		4.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.15
Sift	Benign	0.064	T
Sift4G	Uncertain	0.046	D
Polyphen		0.0020	B
Vest4		0.15
MVP		0.67
MPC		0.69
ClinPred		0.016	T
GERP RS		4.1
Varity_R		0.14
gMVP		0.52
Mutation Taster		=98/2	polymorphism (auto)

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: rs3764758; hg19: chrX-99551784;