rs201671718

Variant names:

• chrX-100407268-T-C
• rs201671718
• NM_001184880.2:c.1330A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP6 BS2

The NM_001184880.2(PCDH19):​c.1330A>G​(p.Thr444Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,210,289 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 63 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.00015 (0 hom. 59 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 3.36
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 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.
• BP6: Variant X-100407268-T-C is Benign according to our data. Variant chrX-100407268-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206296.
• BS2: High AC in GnomAd4 at 15 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.1330A>G	p.Thr444Ala	missense	Exon 1 of 6	NP_001171809.1
	PCDH19	NM_001105243.2		c.1330A>G	p.Thr444Ala	missense	Exon 1 of 5	NP_001098713.1
	PCDH19	NM_020766.3		c.1330A>G	p.Thr444Ala	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.1330A>G	p.Thr444Ala	missense	Exon 1 of 6	ENSP00000362125.4
	PCDH19	ENST00000255531.8	TSL:1	c.1330A>G	p.Thr444Ala	missense	Exon 1 of 5	ENSP00000255531.7
	PCDH19	ENST00000420881.6	TSL:1	c.1330A>G	p.Thr444Ala	missense	Exon 1 of 5	ENSP00000400327.2

Frequencies

GnomAD3 genomes AF: 0.000134 AC: 15 AN: 112069 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000324

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: 0.000263

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000132 AC: 24 AN: 181876 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000154 AC: 169 AN: 1098220 Hom.: 0 Cov.: 33 AF XY: 0.000162 AC XY: 59 AN XY: 363574

African (AFR) AF: 0.00 AC: 0 AN: 26401

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

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.000197 AC: 166 AN: 842106

Other (OTH) AF: 0.0000651 AC: 3 AN: 46096

GnomAD4 genome AF: 0.000134 AC: 15 AN: 112069 Hom.: 0 Cov.: 24 AF XY: 0.000117 AC XY: 4 AN XY: 34283

African (AFR) AF: 0.0000324 AC: 1 AN: 30819

American (AMR) AF: 0.00 AC: 0 AN: 10724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00 AC: 0 AN: 2663

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6080

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

European-Non Finnish (NFE) AF: 0.000263 AC: 14 AN: 53162

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.000133 Hom.: 7

Bravo AF: 0.000113

ESP6500AA AF: 0.000271 AC: 1

ESP6500EA AF: 0.000452 AC: 3

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Developmental and epileptic encephalopathy, 9 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neurodevelopmental disorder with epilepsy (1)
-	1	-	not specified (1)
-	-	1	sporadic NAFE (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.35	N
PhyloP100		3.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Benign	0.16	T
Sift4G	Benign	0.80	T
Polyphen		1.0	D
Vest4		0.68
MVP		0.91
MPC		1.4
ClinPred		0.19	T
GERP RS		6.0
Varity_R		0.26
gMVP		0.36
Mutation Taster		=87/13	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: rs201671718; hg19: chrX-99662266;