rs374593325

Variant names:

• chrX-100406980-G-A
• rs374593325
• NM_001184880.2:c.1618C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001184880.2(PCDH19):​c.1618C>T​(p.Leu540Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,210,262 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 241 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L540L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 19 hem., cov: 24)
  • Exomes 𝑓: 0.00036 (0 hom. 222 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.313
• 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, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 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 Dravet syndrome, developmental and epileptic encephalopathy, 9, X-linked complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01000607).
• BP6: Variant X-100406980-G-A is Benign according to our data. Variant chrX-100406980-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 206334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000232 (26/112053) while in subpopulation SAS AF = 0.00986 (26/2638). AF 95% confidence interval is 0.00691. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 26 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.1618C>T	p.Leu540Phe	missense	Exon 1 of 6	NP_001171809.1
	PCDH19	NM_001105243.2		c.1618C>T	p.Leu540Phe	missense	Exon 1 of 5	NP_001098713.1
	PCDH19	NM_020766.3		c.1618C>T	p.Leu540Phe	missense	Exon 1 of 5	NP_065817.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	ENST00000373034.8	TSL:1 MANE Select	c.1618C>T	p.Leu540Phe	missense	Exon 1 of 6	ENSP00000362125.4
	PCDH19	ENST00000255531.8	TSL:1	c.1618C>T	p.Leu540Phe	missense	Exon 1 of 5	ENSP00000255531.7
	PCDH19	ENST00000420881.6	TSL:1	c.1618C>T	p.Leu540Phe	missense	Exon 1 of 5	ENSP00000400327.2

Frequencies

GnomAD3 genomes AF: 0.000241 AC: 27 AN: 111998 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: 0.0102

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000666 AC: 121 AN: 181793 AF XY: 0.00114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000630

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000361 AC: 397 AN: 1098209 Hom.: 0 Cov.: 33 AF XY: 0.000611 AC XY: 222 AN XY: 363567

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.0000284 AC: 1 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00615 AC: 333 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40502

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4137

European-Non Finnish (NFE) AF: 0.0000499 AC: 42 AN: 842124

Other (OTH) AF: 0.000434 AC: 20 AN: 46098

GnomAD4 genome AF: 0.000232 AC: 26 AN: 112053 Hom.: 0 Cov.: 24 AF XY: 0.000556 AC XY: 19 AN XY: 34203

African (AFR) AF: 0.00 AC: 0 AN: 30887

American (AMR) AF: 0.00 AC: 0 AN: 10668

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3527

South Asian (SAS) AF: 0.00986 AC: 26 AN: 2638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6059

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53197

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000990 AC: 120

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.31
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.050
Sift	Benign	0.10	T
Sift4G	Uncertain	0.021	D
Polyphen		0.25	B
Vest4		0.19
MutPred		0.39		Loss of ubiquitination at K536 (P = 0.0578)
MVP		0.22
MPC		0.65
ClinPred		0.026	T
GERP RS		1.6
PromoterAI		-0.021	Neutral
Varity_R		0.094
gMVP		0.23
Mutation Taster		=97/3	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: rs374593325; hg19: chrX-99661978;