X-100406630-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001184880.2(PCDH19):c.1968T>A(p.Ala656=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,209,785 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 37 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A656A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., 13 hem., cov: 23)
  • Exomes 𝑓: 0.000065 (0 hom. 24 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.116

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant X-100406630-A-T is Benign according to our data. Variant chrX-100406630-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 206300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.116 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000251 (28/111674) while in subpopulation AMR AF= 0.00227 (24/10580). AF 95% confidence interval is 0.00156. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.1968T>A	p.Ala656=	synonymous_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.1968T>A	p.Ala656=	synonymous_variant	1/5
PCDH19	NM_020766.3	c.1968T>A	p.Ala656=	synonymous_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.1968T>A	p.Ala656=	synonymous_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.1968T>A	p.Ala656=	synonymous_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.1968T>A	p.Ala656=	synonymous_variant	1/5	1		A1

Frequencies

GnomAD3 genomes AF: 0.000251 AC: 28 AN: 111674 Hom.: 0 Cov.: 23 AF XY: 0.000384 AC XY: 13 AN XY: 33836

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00227

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000283

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000143 AC: 26 AN: 181568 Hom.: 0 AF XY: 0.0000741 AC XY: 5 AN XY: 67450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000491

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.0000647 AC: 71 AN: 1098111 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 24 AN XY: 363469

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome AF: 0.000251 AC: 28 AN: 111674 Hom.: 0 Cov.: 23 AF XY: 0.000384 AC XY: 13 AN XY: 33836

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00227

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000283

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Developmental and epileptic encephalopathy, 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	1.4
Dann	Benign	0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs776150934; hg19: chrX-99661628;