rs780704524

Variant names:

• chrX-100406574-A-C
• rs780704524
• NM_001184880.2:c.2024T>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 1P and 18B. PP2 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001184880.2(PCDH19):​c.2024T>G​(p.Val675Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,208,654 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts 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. V675M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000032 (0 hom. 7 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.91
• 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: 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 -17 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 developmental and epileptic encephalopathy, 9, X-linked complex neurodevelopmental disorder, Dravet syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07801905).
• BP6: Variant X-100406574-A-C is Benign according to our data. Variant chrX-100406574-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 206301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000319 (35/1096832) while in subpopulation AMR AF = 0.000967 (34/35176). AF 95% confidence interval is 0.00071. There are 0 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 35 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.2024T>G	p.Val675Gly	missense	Exon 1 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.2024T>G	p.Val675Gly	missense	Exon 1 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.2024T>G	p.Val675Gly	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.2024T>G	p.Val675Gly	missense	Exon 1 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.2024T>G	p.Val675Gly	missense	Exon 1 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.2024T>G	p.Val675Gly	missense	Exon 1 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111822 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000947

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000194 AC: 35 AN: 180134 AF XY: 0.0000908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00128

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: 0.0000319 AC: 35 AN: 1096832 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 7 AN XY: 362212

African (AFR) AF: 0.00 AC: 0 AN: 26385

American (AMR) AF: 0.000967 AC: 34 AN: 35176

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 53997

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841021

Other (OTH) AF: 0.0000217 AC: 1 AN: 46062

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111822 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 33980

African (AFR) AF: 0.00 AC: 0 AN: 30687

American (AMR) AF: 0.0000947 AC: 1 AN: 10565

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2671

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6063

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53211

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.000157 AC: 19

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 9 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	PCDH19-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.089	T
Polyphen		0.45	B
Vest4		0.65
MutPred		0.50		Gain of disorder (P = 0.0089)
MVP		0.70
MPC		0.84
ClinPred		0.16	T
GERP RS		5.8
PromoterAI		-0.00010	Neutral
Varity_R		0.64
gMVP		0.81
Mutation Taster		=88/12	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: rs780704524; hg19: chrX-99661572;