NM_001184880.2:c.942G>A

Variant names:

• chrX-100407656-C-T
• rs773740606
• NM_001184880.2:c.942G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001184880.2(PCDH19):​c.942G>A​(p.Leu314Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,210,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 53 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000097 (0 hom., 3 hem., cov: 25)
  • Exomes 𝑓: 0.00015 (0 hom. 50 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0360
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant X-100407656-C-T is Benign according to our data. Variant chrX-100407656-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211840.
• BP7: Synonymous conserved (PhyloP=-0.036 with no splicing effect.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	NM_001184880.2	MANE Select	c.942G>A	p.Leu314Leu	synonymous	Exon 1 of 6	NP_001171809.1
	PCDH19	NM_001105243.2		c.942G>A	p.Leu314Leu	synonymous	Exon 1 of 5	NP_001098713.1
	PCDH19	NM_020766.3		c.942G>A	p.Leu314Leu	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.942G>A	p.Leu314Leu	synonymous	Exon 1 of 6	ENSP00000362125.4
	PCDH19	ENST00000255531.8	TSL:1	c.942G>A	p.Leu314Leu	synonymous	Exon 1 of 5	ENSP00000255531.7
	PCDH19	ENST00000420881.6	TSL:1	c.942G>A	p.Leu314Leu	synonymous	Exon 1 of 5	ENSP00000400327.2

Frequencies

GnomAD3 genomes AF: 0.0000975 AC: 11 AN: 112861 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000605 AC: 11 AN: 181708 AF XY: 0.0000592

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: 0.000123

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000152 AC: 167 AN: 1097881 Hom.: 0 Cov.: 33 AF XY: 0.000138 AC XY: 50 AN XY: 363249

African (AFR) AF: 0.0000758 AC: 2 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40481

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.000190 AC: 160 AN: 841840

Other (OTH) AF: 0.000108 AC: 5 AN: 46086

GnomAD4 genome AF: 0.0000975 AC: 11 AN: 112861 Hom.: 0 Cov.: 25 AF XY: 0.0000857 AC XY: 3 AN XY: 35003

African (AFR) AF: 0.0000965 AC: 3 AN: 31085

American (AMR) AF: 0.00 AC: 0 AN: 10789

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2739

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6235

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000150 AC: 8 AN: 53343

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.0000785 Hom.: 0

Bravo AF: 0.0000642

EpiCase AF: 0.00

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 9 (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.5
DANN	Benign	0.71
PhyloP100		-0.036
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: rs773740606; hg19: chrX-99662654;