X-100408196-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001184880.2(PCDH19):​c.402C>A​(p.Ile134Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0794 in 1,210,548 control chromosomes in the GnomAD database, including 4,215 homozygotes. There are 33,894 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (388 hom., 2925 hem., cov: 25)
  • Exomes 𝑓: 0.080 (3827 hom. 30969 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-100408196-G-T is Benign according to our data. Variant chrX-100408196-G-T is described in ClinVar as Benign. ClinVar VariationId is 93677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	NM_001184880.2	MANE Select	c.402C>A	p.Ile134Ile	synonymous	Exon 1 of 6	NP_001171809.1
	PCDH19	NM_001105243.2		c.402C>A	p.Ile134Ile	synonymous	Exon 1 of 5	NP_001098713.1
	PCDH19	NM_020766.3		c.402C>A	p.Ile134Ile	synonymous	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>A	p.Ile134Ile	synonymous	Exon 1 of 6	ENSP00000362125.4
	PCDH19	ENST00000255531.8	TSL:1	c.402C>A	p.Ile134Ile	synonymous	Exon 1 of 5	ENSP00000255531.7
	PCDH19	ENST00000420881.6	TSL:1	c.402C>A	p.Ile134Ile	synonymous	Exon 1 of 5	ENSP00000400327.2

Frequencies

GnomAD3 genomes AF: 0.0772 AC: 8676 AN: 112357 Hom.: 388 Cov.: 25

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.0145

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.0754

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.0377

Gnomad MID AF: 0.0840

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.0968

GnomAD2 exomes AF: 0.131 AC: 23719 AN: 181650 AF XY: 0.128

Gnomad AFR exome AF: 0.0368

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.0730

Gnomad EAS exome AF: 0.294

Gnomad FIN exome AF: 0.0440

Gnomad NFE exome AF: 0.0576

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0796 AC: 87447 AN: 1098136 Hom.: 3827 Cov.: 33 AF XY: 0.0852 AC XY: 30969 AN XY: 363502

African (AFR) AF: 0.0362 AC: 955 AN: 26403

American (AMR) AF: 0.280 AC: 9852 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.0750 AC: 1454 AN: 19385

East Asian (EAS) AF: 0.266 AC: 8020 AN: 30203

South Asian (SAS) AF: 0.244 AC: 13233 AN: 54149

European-Finnish (FIN) AF: 0.0474 AC: 1919 AN: 40470

Middle Eastern (MID) AF: 0.0870 AC: 360 AN: 4137

European-Non Finnish (NFE) AF: 0.0561 AC: 47256 AN: 842088

Other (OTH) AF: 0.0954 AC: 4398 AN: 46095

GnomAD4 genome AF: 0.0772 AC: 8679 AN: 112412 Hom.: 388 Cov.: 25 AF XY: 0.0845 AC XY: 2925 AN XY: 34604

African (AFR) AF: 0.0372 AC: 1155 AN: 31072

American (AMR) AF: 0.203 AC: 2179 AN: 10753

Ashkenazi Jewish (ASJ) AF: 0.0754 AC: 200 AN: 2652

East Asian (EAS) AF: 0.284 AC: 990 AN: 3485

South Asian (SAS) AF: 0.252 AC: 668 AN: 2648

European-Finnish (FIN) AF: 0.0377 AC: 233 AN: 6187

Middle Eastern (MID) AF: 0.0876 AC: 19 AN: 217

European-Non Finnish (NFE) AF: 0.0578 AC: 3075 AN: 53170

Other (OTH) AF: 0.0975 AC: 150 AN: 1539

Alfa AF: 0.0475 Hom.: 466

Bravo AF: 0.0912

EpiCase AF: 0.0607

EpiControl AF: 0.0578

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Developmental and epileptic encephalopathy, 9 (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.63
DANN	Benign	0.88
PhyloP100		-1.9
PromoterAI		-0.020	Neutral
Mutation Taster		=100/0	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: rs41300169; hg19: chrX-99663194; COSMIC: COSV55263041; COSMIC: COSV55263041;