rs377627937

Variant names:

• chrX-100407943-G-A
• rs377627937
• NM_001184880.2:c.655C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001184880.2(PCDH19):​c.655C>T​(p.Leu219Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,209,602 control chromosomes in the GnomAD database, including 1 homozygotes. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.00012 (1 hom. 38 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0250
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-100407943-G-A is Benign according to our data. Variant chrX-100407943-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.025 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000168 (19/113430) while in subpopulation EAS AF = 0.00112 (4/3574). AF 95% confidence interval is 0.000498. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 19 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	NM_001184880.2	MANE Select	c.655C>T	p.Leu219Leu	synonymous	Exon 1 of 6	NP_001171809.1
	PCDH19	NM_001105243.2		c.655C>T	p.Leu219Leu	synonymous	Exon 1 of 5	NP_001098713.1
	PCDH19	NM_020766.3		c.655C>T	p.Leu219Leu	synonymous	Exon 1 of 5	NP_065817.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	ENST00000373034.8	TSL:1 MANE Select	c.655C>T	p.Leu219Leu	synonymous	Exon 1 of 6	ENSP00000362125.4
	PCDH19	ENST00000255531.8	TSL:1	c.655C>T	p.Leu219Leu	synonymous	Exon 1 of 5	ENSP00000255531.7
	PCDH19	ENST00000420881.6	TSL:1	c.655C>T	p.Leu219Leu	synonymous	Exon 1 of 5	ENSP00000400327.2

Frequencies

GnomAD3 genomes AF: 0.000168 AC: 19 AN: 113430 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000959

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00130

GnomAD2 exomes AF: 0.000100 AC: 18 AN: 179580 AF XY: 0.0000757

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000590

Gnomad FIN exome AF: 0.0000715

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.000450

GnomAD4 exome AF: 0.000119 AC: 130 AN: 1096172 Hom.: 1 Cov.: 33 AF XY: 0.000105 AC XY: 38 AN XY: 362158

African (AFR) AF: 0.0000758 AC: 2 AN: 26402

American (AMR) AF: 0.0000852 AC: 3 AN: 35205

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

East Asian (EAS) AF: 0.000530 AC: 16 AN: 30206

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38495

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

European-Non Finnish (NFE) AF: 0.0000226 AC: 19 AN: 842109

Other (OTH) AF: 0.00193 AC: 89 AN: 46084

GnomAD4 genome AF: 0.000168 AC: 19 AN: 113430 Hom.: 0 Cov.: 24 AF XY: 0.0000562 AC XY: 2 AN XY: 35562

African (AFR) AF: 0.0000959 AC: 3 AN: 31282

American (AMR) AF: 0.000919 AC: 10 AN: 10880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2665

East Asian (EAS) AF: 0.00112 AC: 4 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2805

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6343

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53414

Other (OTH) AF: 0.00130 AC: 2 AN: 1543

Alfa AF: 0.000285 Hom.: 1

Bravo AF: 0.000193

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.81
DANN	Benign	0.65
PhyloP100		0.025
Mutation Taster		=100/0	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: rs377627937; hg19: chrX-99662941;