NM_001184880.2:c.2790T>C

Variant names:

• chrX-100341961-A-G
• rs375759744
• NM_001184880.2:c.2790T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001184880.2(PCDH19):​c.2790T>C​(p.Ala930Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,208,423 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 88 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 0.00021 (0 hom., 12 hem., cov: 24)
  • Exomes 𝑓: 0.00021 (0 hom. 76 hem.)
• Consequence: PCDH19 NM_001184880.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0800
• Publications: 0 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, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant X-100341961-A-G is Benign according to our data. Variant chrX-100341961-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 380720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.08 with no splicing effect.
• BS2: High AC in GnomAd4 at 24 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.2790T>C	p.Ala930Ala	synonymous	Exon 5 of 6	NP_001171809.1	Q8TAB3-1
	PCDH19	NM_001105243.2		c.2649T>C	p.Ala883Ala	synonymous	Exon 4 of 5	NP_001098713.1	Q8TAB3-2
	PCDH19	NM_020766.3		c.2646T>C	p.Ala882Ala	synonymous	Exon 4 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.2790T>C	p.Ala930Ala	synonymous	Exon 5 of 6	ENSP00000362125.4	Q8TAB3-1
	PCDH19	ENST00000255531.8	TSL:1	c.2649T>C	p.Ala883Ala	synonymous	Exon 4 of 5	ENSP00000255531.7	Q8TAB3-2
	PCDH19	ENST00000420881.6	TSL:1	c.2646T>C	p.Ala882Ala	synonymous	Exon 4 of 5	ENSP00000400327.2	Q8TAB3-3

Frequencies

GnomAD3 genomes AF: 0.000214 AC: 24 AN: 112178 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00867

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000385 AC: 70 AN: 181747 AF XY: 0.000414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000731

Gnomad ASJ exome AF: 0.00802

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000859

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000208 AC: 228 AN: 1096245 Hom.: 0 Cov.: 31 AF XY: 0.000210 AC XY: 76 AN XY: 361629

African (AFR) AF: 0.00 AC: 0 AN: 26361

American (AMR) AF: 0.0000568 AC: 2 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00872 AC: 169 AN: 19374

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54101

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.0000345 AC: 29 AN: 840312

Other (OTH) AF: 0.000608 AC: 28 AN: 46034

GnomAD4 genome AF: 0.000214 AC: 24 AN: 112178 Hom.: 0 Cov.: 24 AF XY: 0.000350 AC XY: 12 AN XY: 34322

African (AFR) AF: 0.00 AC: 0 AN: 30868

American (AMR) AF: 0.00 AC: 0 AN: 10571

Ashkenazi Jewish (ASJ) AF: 0.00867 AC: 23 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53247

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.00135 Hom.: 8

Bravo AF: 0.000257

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.4
DANN	Benign	0.59
PhyloP100		-0.080
Mutation Taster		=87/13	polymorphism

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: rs375759744; hg19: chrX-99596959;