rs1953337

Variant names:

• chrX-100406971-G-A
• rs1953337
• NM_001184880.2:c.1627C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001184880.2(PCDH19):​c.1627C>T​(p.Leu543Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,209,634 control chromosomes in the GnomAD database, including 30,302 homozygotes. There are 98,094 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2017 hom., 5870 hem., cov: 23)
  • Exomes 𝑓: 0.26 (28285 hom. 92224 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.97
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-100406971-G-A is Benign according to our data. Variant chrX-100406971-G-A is described in ClinVar as Benign. ClinVar VariationId is 93671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

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.1627C>T	p.Leu543Leu	synonymous	Exon 1 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.1627C>T	p.Leu543Leu	synonymous	Exon 1 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.1627C>T	p.Leu543Leu	synonymous	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.1627C>T	p.Leu543Leu	synonymous	Exon 1 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.1627C>T	p.Leu543Leu	synonymous	Exon 1 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.1627C>T	p.Leu543Leu	synonymous	Exon 1 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.188 AC: 20972 AN: 111426 Hom.: 2015 Cov.: 23

Gnomad AFR AF: 0.0468

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.00141

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.159

GnomAD2 exomes AF: 0.209 AC: 38052 AN: 181671 AF XY: 0.203

Gnomad AFR exome AF: 0.0453

Gnomad AMR exome AF: 0.225

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.0000738

Gnomad FIN exome AF: 0.275

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.262 AC: 287428 AN: 1098151 Hom.: 28285 Cov.: 34 AF XY: 0.254 AC XY: 92224 AN XY: 363521

African (AFR) AF: 0.0414 AC: 1093 AN: 26402

American (AMR) AF: 0.219 AC: 7727 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 3267 AN: 19386

East Asian (EAS) AF: 0.000298 AC: 9 AN: 30206

South Asian (SAS) AF: 0.0872 AC: 4721 AN: 54146

European-Finnish (FIN) AF: 0.274 AC: 11096 AN: 40494

Middle Eastern (MID) AF: 0.105 AC: 435 AN: 4137

European-Non Finnish (NFE) AF: 0.296 AC: 248897 AN: 842085

Other (OTH) AF: 0.221 AC: 10183 AN: 46091

GnomAD4 genome AF: 0.188 AC: 20970 AN: 111483 Hom.: 2017 Cov.: 23 AF XY: 0.174 AC XY: 5870 AN XY: 33679

African (AFR) AF: 0.0467 AC: 1441 AN: 30828

American (AMR) AF: 0.174 AC: 1840 AN: 10593

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 463 AN: 2641

East Asian (EAS) AF: 0.00142 AC: 5 AN: 3524

South Asian (SAS) AF: 0.0619 AC: 163 AN: 2635

European-Finnish (FIN) AF: 0.257 AC: 1523 AN: 5925

Middle Eastern (MID) AF: 0.112 AC: 24 AN: 215

European-Non Finnish (NFE) AF: 0.285 AC: 15091 AN: 52932

Other (OTH) AF: 0.157 AC: 238 AN: 1514

Alfa AF: 0.214 Hom.: 7644

Bravo AF: 0.179

EpiCase AF: 0.258

EpiControl AF: 0.253

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Developmental and epileptic encephalopathy, 9 (4)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.8
DANN	Benign	0.75
PhyloP100		3.0
PromoterAI		-0.017	Neutral
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: rs1953337; hg19: chrX-99661969; COSMIC: COSV55257660; COSMIC: COSV55257660;