X-100403557-T-G

Position:

• chrX-100403557-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001184880.2(PCDH19):​c.2255A>C​(p.Lys752Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,143 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11786622).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.2255A>C	p.Lys752Thr	missense_variant	2/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.2148-706A>C		intron_variant			NP_001098713.1
PCDH19	NM_020766.3	c.2148-706A>C		intron_variant			NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.2255A>C	p.Lys752Thr	missense_variant	2/6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.2148-706A>C		intron_variant		1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.2148-706A>C		intron_variant		1		ENSP00000400327.2
PCDH19	ENST00000636150.1	c.66-982A>C		intron_variant		5		ENSP00000490463.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000574 AC: 1 AN: 174306 Hom.: 0 AF XY: 0.0000153 AC XY: 1 AN XY: 65478

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 SAS exome AF: 0.0000536

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096143 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 2 AN XY: 362317

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.023	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.099
Sift	Benign	0.095	T
Sift4G	Benign	0.11	T
Polyphen		0.24	B
Vest4		0.17
MutPred		0.43		Loss of ubiquitination at K752 (P = 0.0071);
MVP		0.54
MPC		0.61
ClinPred		0.23	T
GERP RS		5.7
Varity_R		0.29
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1452944576; hg19: chrX-99658555;