rs748581653

Variant names:

• chrX-100296851-C-T
• rs748581653
• NM_001184880.2:c.2873G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-100296851-C-T
• chrX-100296851-C-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.2873G>A​(p.Arg958Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,206,546 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 82 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R958W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.00017 (0 hom. 77 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.10
• Publications: 10 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=0.035001665).
• BP6: Variant X-100296851-C-T is Benign according to our data. Variant chrX-100296851-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 206362.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 = 0.0000988 (11/111336) while in subpopulation SAS AF = 0.00195 (5/2561). AF 95% confidence interval is 0.000769. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 11 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.2873G>A	p.Arg958Gln	missense	Exon 6 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.2732G>A	p.Arg911Gln	missense	Exon 5 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.2729G>A	p.Arg910Gln	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.2873G>A	p.Arg958Gln	missense	Exon 6 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.2732G>A	p.Arg911Gln	missense	Exon 5 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.2729G>A	p.Arg910Gln	missense	Exon 5 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111282 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00195

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.0000755

Gnomad OTH AF: 0.000667

GnomAD2 exomes AF: 0.000194 AC: 35 AN: 180554 AF XY: 0.000284

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: 0.0000497

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000174 AC: 191 AN: 1095210 Hom.: 0 Cov.: 29 AF XY: 0.000214 AC XY: 77 AN XY: 360638

African (AFR) AF: 0.000152 AC: 4 AN: 26333

American (AMR) AF: 0.0000284 AC: 1 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30190

South Asian (SAS) AF: 0.00155 AC: 84 AN: 54069

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00667 AC: 27 AN: 4051

European-Non Finnish (NFE) AF: 0.0000762 AC: 64 AN: 839486

Other (OTH) AF: 0.000239 AC: 11 AN: 45976

GnomAD4 genome AF: 0.0000988 AC: 11 AN: 111336 Hom.: 0 Cov.: 22 AF XY: 0.000149 AC XY: 5 AN XY: 33544

African (AFR) AF: 0.0000326 AC: 1 AN: 30628

American (AMR) AF: 0.00 AC: 0 AN: 10535

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3523

South Asian (SAS) AF: 0.00195 AC: 5 AN: 2561

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6038

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

European-Non Finnish (NFE) AF: 0.0000755 AC: 4 AN: 52984

Other (OTH) AF: 0.000658 AC: 1 AN: 1519

Alfa AF: 0.0000359 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.000289 AC: 35

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.51	N
PhyloP100		3.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.040
Sift	Benign	0.16	T
Sift4G	Benign	0.20	T
Polyphen		0.12	B
Vest4		0.24
MutPred		0.33		Gain of sheet (P = 0.0049)
MVP		0.59
MPC		0.59
ClinPred		0.023	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.16
Mutation Taster		=98/2	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: rs748581653; hg19: chrX-99551849; COSMIC: COSV55269911; COSMIC: COSV55269911;