rs191333060

Variant names:

• chrX-100296405-G-C
• rs191333060
• NM_001184880.2:c.3319C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-100296405-G-C
• chrX-100296405-G-A

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.3319C>G​(p.Arg1107Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,208,998 control chromosomes in the GnomAD database, including 3 homozygotes. There are 749 hemizygotes in GnomAD. In-silico tool predicts 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. R1107H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 32 hem., cov: 23)
  • Exomes 𝑓: 0.0019 (3 hom. 717 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 7.28
• Publications: 11 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=0.026628107).
• BP6: Variant X-100296405-G-C is Benign according to our data. Variant chrX-100296405-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93675.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 = 0.00123 (137/111404) while in subpopulation NFE AF = 0.00215 (114/53091). AF 95% confidence interval is 0.00183. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 137 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.3319C>G	p.Arg1107Gly	missense	Exon 6 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.3178C>G	p.Arg1060Gly	missense	Exon 5 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.3175C>G	p.Arg1059Gly	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.3319C>G	p.Arg1107Gly	missense	Exon 6 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.3178C>G	p.Arg1060Gly	missense	Exon 5 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.3175C>G	p.Arg1059Gly	missense	Exon 5 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 137 AN: 111346 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000570

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000392

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00404

GnomAD2 exomes AF: 0.00126 AC: 228 AN: 181589 AF XY: 0.00142

Gnomad AFR exome AF: 0.000242

Gnomad AMR exome AF: 0.000767

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000628

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00191 AC: 2101 AN: 1097594 Hom.: 3 Cov.: 30 AF XY: 0.00198 AC XY: 717 AN XY: 362964

African (AFR) AF: 0.000379 AC: 10 AN: 26389

American (AMR) AF: 0.000994 AC: 35 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.000314 AC: 17 AN: 54134

European-Finnish (FIN) AF: 0.000222 AC: 9 AN: 40521

Middle Eastern (MID) AF: 0.00846 AC: 35 AN: 4136

European-Non Finnish (NFE) AF: 0.00226 AC: 1898 AN: 841545

Other (OTH) AF: 0.00210 AC: 97 AN: 46081

GnomAD4 genome AF: 0.00123 AC: 137 AN: 111404 Hom.: 0 Cov.: 23 AF XY: 0.000953 AC XY: 32 AN XY: 33588

African (AFR) AF: 0.000293 AC: 9 AN: 30671

American (AMR) AF: 0.000569 AC: 6 AN: 10541

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3526

South Asian (SAS) AF: 0.000393 AC: 1 AN: 2543

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5986

Middle Eastern (MID) AF: 0.00465 AC: 1 AN: 215

European-Non Finnish (NFE) AF: 0.00215 AC: 114 AN: 53091

Other (OTH) AF: 0.00398 AC: 6 AN: 1506

Alfa AF: 0.00124 Hom.: 10

Bravo AF: 0.00124

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00242 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00290 AC: 19

ExAC AF: 0.00152 AC: 184

EpiCase AF: 0.00224

EpiControl AF: 0.00237

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)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
1	-	-	Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.15
Sift	Uncertain	0.017	D
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.47
MVP		0.49
MPC		1.4
ClinPred		0.035	T
GERP RS		4.6
Varity_R		0.39
gMVP		0.57
Mutation Taster		=99/1	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: rs191333060; hg19: chrX-99551403;