X-100296269-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001184880.2(PCDH19):c.*8T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000566 in 1,180,965 control chromosomes in the GnomAD database, including 3 homozygotes. There are 174 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., 89 hem., cov: 23)
  • Exomes 𝑓: 0.00033 (3 hom. 85 hem.)
• Consequence: PCDH19 NM_001184880.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0850

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-100296269-A-G is Benign according to our data. Variant chrX-100296269-A-G is described in ClinVar as [Benign]. Clinvar id is 138595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100296269-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00283 (317/112102) while in subpopulation AFR AF= 0.0095 (293/30854). AF 95% confidence interval is 0.0086. There are 0 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 89 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.*8T>C		3_prime_UTR_variant	6/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.*8T>C		3_prime_UTR_variant	5/5
PCDH19	NM_020766.3	c.*8T>C		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.*8T>C		3_prime_UTR_variant	6/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.*8T>C		3_prime_UTR_variant	5/5	1		P5
PCDH19	ENST00000420881.6	c.*8T>C		3_prime_UTR_variant	5/5	1		A1
PCDH19	ENST00000464981.1	c.*8T>C		3_prime_UTR_variant, NMD_transcript_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 317 AN: 112050 Hom.: 0 Cov.: 23 AF XY: 0.00260 AC XY: 89 AN XY: 34218

Gnomad AFR AF: 0.00952

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00188

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: 0.00

Gnomad OTH AF: 0.00263

GnomAD3 exomes AF: 0.000876 AC: 159 AN: 181466 Hom.: 1 AF XY: 0.000638 AC XY: 43 AN XY: 67420

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.000913

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000329 AC: 352 AN: 1068863 Hom.: 3 Cov.: 26 AF XY: 0.000251 AC XY: 85 AN XY: 338411

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000935

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000245

Gnomad4 OTH exome AF: 0.000753

GnomAD4 genome AF: 0.00283 AC: 317 AN: 112102 Hom.: 0 Cov.: 23 AF XY: 0.00260 AC XY: 89 AN XY: 34280

Gnomad4 AFR AF: 0.00950

Gnomad4 AMR AF: 0.00188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00260

Alfa AF: 0.00133 Hom.: 4

Bravo AF: 0.00342

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2013	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	3.0
Dann	Benign	0.67

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: rs145987305; hg19: chrX-99551267;