NM_001184880.2:c.3280C>G

Variant names:

• chrX-100296444-G-C
• rs184545774
• NM_001184880.2:c.3280C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001184880.2(PCDH19):​c.3280C>G​(p.Leu1094Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,209,488 control chromosomes in the GnomAD database, including 2 homozygotes. There are 951 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., 46 hem., cov: 22)
  • Exomes 𝑓: 0.0026 (2 hom. 905 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.83
• 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=0.0055009425).
• BP6: Variant X-100296444-G-C is Benign according to our data. Variant chrX-100296444-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0015 (167/111375) while in subpopulation NFE AF = 0.00232 (123/53088). AF 95% confidence interval is 0.00198. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 167 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.3280C>G	p.Leu1094Val	missense	Exon 6 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.3139C>G	p.Leu1047Val	missense	Exon 5 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.3136C>G	p.Leu1046Val	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.3280C>G	p.Leu1094Val	missense	Exon 6 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.3139C>G	p.Leu1047Val	missense	Exon 5 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.3136C>G	p.Leu1046Val	missense	Exon 5 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 167 AN: 111318 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00219

Gnomad ASJ AF: 0.00304

Gnomad EAS AF: 0.000564

Gnomad SAS AF: 0.000391

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.000669

GnomAD2 exomes AF: 0.00148 AC: 269 AN: 181515 AF XY: 0.00150

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.000402

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.000443

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00256 AC: 2815 AN: 1098113 Hom.: 2 Cov.: 30 AF XY: 0.00249 AC XY: 905 AN XY: 363469

African (AFR) AF: 0.000227 AC: 6 AN: 26402

American (AMR) AF: 0.000540 AC: 19 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00201 AC: 39 AN: 19386

East Asian (EAS) AF: 0.00103 AC: 31 AN: 30205

South Asian (SAS) AF: 0.000997 AC: 54 AN: 54143

European-Finnish (FIN) AF: 0.0000987 AC: 4 AN: 40519

Middle Eastern (MID) AF: 0.00387 AC: 16 AN: 4137

European-Non Finnish (NFE) AF: 0.00302 AC: 2540 AN: 842021

Other (OTH) AF: 0.00230 AC: 106 AN: 46093

GnomAD4 genome AF: 0.00150 AC: 167 AN: 111375 Hom.: 0 Cov.: 22 AF XY: 0.00137 AC XY: 46 AN XY: 33565

African (AFR) AF: 0.000261 AC: 8 AN: 30627

American (AMR) AF: 0.00218 AC: 23 AN: 10530

Ashkenazi Jewish (ASJ) AF: 0.00304 AC: 8 AN: 2635

East Asian (EAS) AF: 0.000566 AC: 2 AN: 3533

South Asian (SAS) AF: 0.000392 AC: 1 AN: 2551

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5995

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.00232 AC: 123 AN: 53088

Other (OTH) AF: 0.000660 AC: 1 AN: 1515

Alfa AF: 0.00223 Hom.: 46

Bravo AF: 0.00171

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00346 AC: 10

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00351 AC: 23

ExAC AF: 0.00150 AC: 181

EpiCase AF: 0.00202

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Developmental and epileptic encephalopathy, 9 (4)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.25
DEOGEN2	Benign	0.020	T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.086
Sift	Benign	0.67	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.094
MVP		0.37
MPC		0.51
ClinPred		0.0036	T
GERP RS		1.4
Varity_R		0.079
gMVP		0.21
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: rs184545774; hg19: chrX-99551442;