rs140313320

chrX-18625140-G-AchrX-18625140-G-C

Variant summary

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

The NM_001323289.2(CDKL5):c.2389G>A(p.Asp797Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000706 in 1,204,742 control chromosomes in the GnomAD database, including 1 homozygotes. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D797H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000073 (1 hom. 19 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.89

Genes affected

CDKL5 (HGNC:11411): (cyclin dependent kinase like 5) This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044061214).
• BP6: Variant X-18625140-G-A is Benign according to our data. Variant chrX-18625140-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 189533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000073 (80/1095349) while in subpopulation AMR AF= 0.00151 (53/35199). AF 95% confidence interval is 0.00118. There are 1 homozygotes in gnomad4_exome. There are 19 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.2389G>A	p.Asp797Asn	missense_variant	17/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.2389G>A	p.Asp797Asn	missense_variant	18/22
CDKL5	NM_003159.3	c.2389G>A	p.Asp797Asn	missense_variant	17/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.2389G>A	p.Asp797Asn	missense_variant	17/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000457 AC: 5 AN: 109344 Hom.: 0 Cov.: 22 AF XY: 0.0000315 AC XY: 1 AN XY: 31698

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000985

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: 0.0000570

Gnomad OTH AF: 0.000682

GnomAD3 exomes AF: 0.000279 AC: 51 AN: 182916 Hom.: 1 AF XY: 0.000148 AC XY: 10 AN XY: 67428

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00146

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: 0.0000244

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.0000730 AC: 80 AN: 1095349 Hom.: 1 Cov.: 29 AF XY: 0.0000526 AC XY: 19 AN XY: 360925

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.00151

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000202

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000457 AC: 5 AN: 109393 Hom.: 0 Cov.: 22 AF XY: 0.0000315 AC XY: 1 AN XY: 31757

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000984

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000570

Gnomad4 OTH AF: 0.000674

Bravo AF: 0.0000680

ExAC AF: 0.000338 AC: 41

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	curation	RettBASE	May 15, 2014	Found in unaffected male and normal population, In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = possibly damaging, AlignGVGD = benign (C0) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2024	Variant summary: Variant summary: The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16. 2/4 in silico tools predict benign outcome for this variant but 5/5 splice prediction tools predict a significant impact on normal splicing. A reverse transcription���PCR study indicated that it is likely to cause a donor site splicing error (Mak_1998). This variant was found in 1/121374 control chromosomes (including ExAC) at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been found in several FH patients including evidence of cosegregation with disease. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -

Developmental and epileptic encephalopathy, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2020

This variant is associated with the following publications: (PMID: 22867051) -

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.026	T;T;T;.
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.044	T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.6	L;.;L;L
MutationTaster	Benign	0.65	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.73	N;.;N;.
REVEL	Benign	0.21
Sift	Benign	0.090	T;.;T;.
Sift4G	Uncertain	0.030	D;.;D;T
Polyphen		0.96	P;.;P;.
Vest4		0.23
MutPred		0.19		Gain of MoRF binding (P = 0.0487);Gain of MoRF binding (P = 0.0487);Gain of MoRF binding (P = 0.0487);Gain of MoRF binding (P = 0.0487);
MVP		0.89
MPC		0.34
ClinPred		0.030	T
GERP RS		6.0
Varity_R		0.098
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs140313320; hg19: chrX-18643260;