chrX-100296749-G-A

Variant names:

• chrX-100296749-G-A
• rs371109150
• NM_001184880.2:c.2975C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001184880.2(PCDH19):​c.2975C>T​(p.Ala992Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000091 in 1,209,235 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A992T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 1 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.52
• Publications: 4 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 -5 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=0.14945772).
• BS2: High AC in GnomAdExome4 at 7 AD,XL,Unknown 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.2975C>T	p.Ala992Val	missense	Exon 6 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.2834C>T	p.Ala945Val	missense	Exon 5 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.2831C>T	p.Ala944Val	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.2975C>T	p.Ala992Val	missense	Exon 6 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.2834C>T	p.Ala945Val	missense	Exon 5 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.2831C>T	p.Ala944Val	missense	Exon 5 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.0000359 AC: 4 AN: 111514 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000979

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000330 AC: 6 AN: 181576 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000738

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1097721 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363091

African (AFR) AF: 0.0000758 AC: 2 AN: 26391

American (AMR) AF: 0.00 AC: 0 AN: 35207

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

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54130

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4087

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841715

Other (OTH) AF: 0.0000217 AC: 1 AN: 46069

GnomAD4 genome AF: 0.0000359 AC: 4 AN: 111514 Hom.: 0 Cov.: 22 AF XY: 0.0000297 AC XY: 1 AN XY: 33670

African (AFR) AF: 0.0000979 AC: 3 AN: 30638

American (AMR) AF: 0.00 AC: 0 AN: 10549

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3538

South Asian (SAS) AF: 0.00 AC: 0 AN: 2587

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53107

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000276 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 9 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.27
DEOGEN2	Benign	0.020	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N
PhyloP100		6.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.14
Sift	Benign	0.57	T
Sift4G	Benign	1.0	T
Polyphen		0.40	B
Vest4		0.11
MVP		0.56
MPC		0.51
ClinPred		0.065	T
GERP RS		5.8
Varity_R		0.11
gMVP		0.39
Mutation Taster		=96/4	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: rs371109150; hg19: chrX-99551747; COSMIC: COSV55264544; COSMIC: COSV55264544;