X-100408517-G-C

Variant names:

• chrX-100408517-G-C
• rs56307810
• NM_001184880.2:c.81C>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001184880.2(PCDH19):​c.81C>G​(p.Tyr27*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y27Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PCDH19 NM_001184880.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.41
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 413 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-100408517-G-C is Pathogenic according to our data. Variant chrX-100408517-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 872431.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.81C>G	p.Tyr27*	stop_gained	Exon 1 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.81C>G	p.Tyr27*	stop_gained	Exon 1 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.81C>G	p.Tyr27*	stop_gained	Exon 1 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.81C>G	p.Tyr27*	stop_gained	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.81C>G	p.Tyr27*	stop_gained	Exon 1 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.81C>G	p.Tyr27*	stop_gained	Exon 1 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1087999 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 357109

African (AFR) AF: 0.00 AC: 0 AN: 26305

American (AMR) AF: 0.00 AC: 0 AN: 34763

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19282

East Asian (EAS) AF: 0.00 AC: 0 AN: 29987

South Asian (SAS) AF: 0.00 AC: 0 AN: 53327

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839578

Other (OTH) AF: 0.00 AC: 0 AN: 45816

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		4.4
Vest4		0.83
GERP RS		4.6
PromoterAI		-0.012	Neutral
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs56307810; hg19: chrX-99663515;