X-100408517-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001184880.2(PCDH19):​c.81C>T​(p.Tyr27Tyr) variant causes a synonymous change. The variant allele was found at a frequency of 0.0123 in 1,199,655 control chromosomes in the GnomAD database, including 89 homozygotes. There are 4,537 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 0.0091 (7 hom., 271 hem., cov: 23)
  • Exomes 𝑓: 0.013 (82 hom. 4266 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-100408517-G-A is Benign according to our data. Variant chrX-100408517-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00912 (1018/111674) while in subpopulation NFE AF = 0.0153 (812/52957). AF 95% confidence interval is 0.0145. There are 7 homozygotes in GnomAd4. There are 271 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1018 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.81C>T	p.Tyr27Tyr	synonymous	Exon 1 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.81C>T	p.Tyr27Tyr	synonymous	Exon 1 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.81C>T	p.Tyr27Tyr	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.81C>T	p.Tyr27Tyr	synonymous	Exon 1 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.81C>T	p.Tyr27Tyr	synonymous	Exon 1 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.81C>T	p.Tyr27Tyr	synonymous	Exon 1 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1018 AN: 111630 Hom.: 7 Cov.: 23

Gnomad AFR AF: 0.00218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00267

Gnomad FIN AF: 0.0178

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.00536

GnomAD2 exomes AF: 0.00825 AC: 1296 AN: 157008 AF XY: 0.00671

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.000990

Gnomad ASJ exome AF: 0.000429

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.00675

GnomAD4 exome AF: 0.0126 AC: 13686 AN: 1087981 Hom.: 82 Cov.: 32 AF XY: 0.0119 AC XY: 4266 AN XY: 357101

African (AFR) AF: 0.00171 AC: 45 AN: 26305

American (AMR) AF: 0.00158 AC: 55 AN: 34761

Ashkenazi Jewish (ASJ) AF: 0.000519 AC: 10 AN: 19282

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

South Asian (SAS) AF: 0.00238 AC: 127 AN: 53327

European-Finnish (FIN) AF: 0.0229 AC: 798 AN: 34822

Middle Eastern (MID) AF: 0.00170 AC: 7 AN: 4117

European-Non Finnish (NFE) AF: 0.0145 AC: 12210 AN: 839566

Other (OTH) AF: 0.00947 AC: 434 AN: 45814

GnomAD4 genome AF: 0.00912 AC: 1018 AN: 111674 Hom.: 7 Cov.: 23 AF XY: 0.00800 AC XY: 271 AN XY: 33874

African (AFR) AF: 0.00217 AC: 67 AN: 30855

American (AMR) AF: 0.00159 AC: 17 AN: 10716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3480

South Asian (SAS) AF: 0.00268 AC: 7 AN: 2611

European-Finnish (FIN) AF: 0.0178 AC: 107 AN: 6003

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0153 AC: 812 AN: 52957

Other (OTH) AF: 0.00529 AC: 8 AN: 1511

Alfa AF: 0.0117 Hom.: 91

Bravo AF: 0.00703

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.1
DANN	Benign	0.73
PhyloP100		4.4
PromoterAI		0.018	Neutral
Mutation Taster		=100/0	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: rs56307810; hg19: chrX-99663515;