rs201713027

Variant names:

• chrX-100407829-C-G
• rs201713027
• NM_001184880.2:c.769G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-100407829-C-G
• chrX-100407829-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_001184880.2(PCDH19):​c.769G>C​(p.Val257Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000591 in 1,211,112 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 246 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., 13 hem., cov: 24)
  • Exomes 𝑓: 0.00059 (0 hom. 233 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 3.33
• Publications: 3 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 -10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 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 developmental and epileptic encephalopathy, 9, X-linked complex neurodevelopmental disorder, Dravet syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.040152162).
• BP6: Variant X-100407829-C-G is Benign according to our data. Variant chrX-100407829-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193196.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000602 (68/112931) while in subpopulation NFE AF = 0.00114 (61/53322). AF 95% confidence interval is 0.000914. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 68 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.769G>C	p.Val257Leu	missense	Exon 1 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.769G>C	p.Val257Leu	missense	Exon 1 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.769G>C	p.Val257Leu	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.769G>C	p.Val257Leu	missense	Exon 1 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.769G>C	p.Val257Leu	missense	Exon 1 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.769G>C	p.Val257Leu	missense	Exon 1 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.000602 AC: 68 AN: 112877 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000926

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000641

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00114

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000567 AC: 103 AN: 181777 AF XY: 0.000533

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.000944

Gnomad OTH exome AF: 0.000448

GnomAD4 exome AF: 0.000590 AC: 648 AN: 1098181 Hom.: 0 Cov.: 33 AF XY: 0.000641 AC XY: 233 AN XY: 363537

African (AFR) AF: 0.0000757 AC: 2 AN: 26403

American (AMR) AF: 0.0000284 AC: 1 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19386

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

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54148

European-Finnish (FIN) AF: 0.00109 AC: 44 AN: 40497

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

European-Non Finnish (NFE) AF: 0.000695 AC: 585 AN: 842106

Other (OTH) AF: 0.000239 AC: 11 AN: 46092

GnomAD4 genome AF: 0.000602 AC: 68 AN: 112931 Hom.: 0 Cov.: 24 AF XY: 0.000370 AC XY: 13 AN XY: 35101

African (AFR) AF: 0.0000642 AC: 2 AN: 31166

American (AMR) AF: 0.0000925 AC: 1 AN: 10815

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.00 AC: 0 AN: 2734

European-Finnish (FIN) AF: 0.000641 AC: 4 AN: 6241

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00114 AC: 61 AN: 53322

Other (OTH) AF: 0.00 AC: 0 AN: 1540

Alfa AF: 0.000994 Hom.: 21

Bravo AF: 0.000332

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00173 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000299 AC: 2

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.000491

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	2	not specified (3)
-	-	1	Developmental and epileptic encephalopathy, 9 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	PCDH19-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.18
Sift	Benign	0.47	T
Sift4G	Benign	0.35	T
Polyphen		1.0	D
Vest4		0.33
MVP		0.58
MPC		1.3
ClinPred		0.046	T
GERP RS		6.0
Varity_R		0.65
gMVP		0.78
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201713027; hg19: chrX-99662827;