chrX-100406915-C-T

Variant names:

• chrX-100406915-C-T
• rs192354176
• NM_001184880.2:c.1683G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001184880.2(PCDH19):​c.1683G>A​(p.Pro561Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,210,006 control chromosomes in the GnomAD database, including 8 homozygotes. There are 1,265 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., 68 hem., cov: 23)
  • Exomes 𝑓: 0.0033 (8 hom. 1197 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.47
• Publications: 1 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-100406915-C-T is Benign according to our data. Variant chrX-100406915-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00273 (305/111879) while in subpopulation NFE AF = 0.00431 (229/53104). AF 95% confidence interval is 0.00385. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 305 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	NM_001184880.2	MANE Select	c.1683G>A	p.Pro561Pro	synonymous	Exon 1 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.1683G>A	p.Pro561Pro	synonymous	Exon 1 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.1683G>A	p.Pro561Pro	synonymous	Exon 1 of 5	NP_065817.2	Q8TAB3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH19	ENST00000373034.8	TSL:1 MANE Select	c.1683G>A	p.Pro561Pro	synonymous	Exon 1 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.1683G>A	p.Pro561Pro	synonymous	Exon 1 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.1683G>A	p.Pro561Pro	synonymous	Exon 1 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 305 AN: 111825 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00358

Gnomad ASJ AF: 0.00716

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000377

Gnomad FIN AF: 0.000822

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00285 AC: 517 AN: 181625 AF XY: 0.00258

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00138

Gnomad NFE exome AF: 0.00446

Gnomad OTH exome AF: 0.00515

GnomAD4 exome AF: 0.00333 AC: 3657 AN: 1098127 Hom.: 8 Cov.: 32 AF XY: 0.00329 AC XY: 1197 AN XY: 363487

African (AFR) AF: 0.0000758 AC: 2 AN: 26400

American (AMR) AF: 0.00227 AC: 80 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00712 AC: 138 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.000425 AC: 23 AN: 54148

European-Finnish (FIN) AF: 0.00202 AC: 82 AN: 40516

Middle Eastern (MID) AF: 0.00435 AC: 18 AN: 4137

European-Non Finnish (NFE) AF: 0.00372 AC: 3130 AN: 842034

Other (OTH) AF: 0.00399 AC: 184 AN: 46093

GnomAD4 genome AF: 0.00273 AC: 305 AN: 111879 Hom.: 0 Cov.: 23 AF XY: 0.00200 AC XY: 68 AN XY: 34059

African (AFR) AF: 0.000227 AC: 7 AN: 30828

American (AMR) AF: 0.00358 AC: 38 AN: 10629

Ashkenazi Jewish (ASJ) AF: 0.00716 AC: 19 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3529

South Asian (SAS) AF: 0.000378 AC: 1 AN: 2645

European-Finnish (FIN) AF: 0.000822 AC: 5 AN: 6082

Middle Eastern (MID) AF: 0.00465 AC: 1 AN: 215

European-Non Finnish (NFE) AF: 0.00431 AC: 229 AN: 53104

Other (OTH) AF: 0.00330 AC: 5 AN: 1513

Alfa AF: 0.00407 Hom.: 46

Bravo AF: 0.00352

EpiCase AF: 0.00447

EpiControl AF: 0.00551

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Developmental and epileptic encephalopathy, 9 (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.4
DANN	Benign	0.86
PhyloP100		-2.5
PromoterAI		0.012	Neutral
Mutation Taster		=96/4	polymorphism (auto)

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: rs192354176; hg19: chrX-99661913;