X-18598609-A-C

Variant names:

• chrX-18598609-A-C
• rs756721244
• NM_001323289.2:c.973A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001323289.2(CDKL5):​c.973A>C​(p.Asn325His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N325D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.48
• Publications: 0 publications found

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]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3463168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.973A>C	p.Asn325His	missense_variant	Exon 11 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.973A>C	p.Asn325His	missense_variant	Exon 12 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.973A>C	p.Asn325His	missense_variant	Exon 11 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.973A>C	p.Asn325His	missense_variant	Exon 11 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.35	T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.8	L;.;.;L;.;L
PhyloP100		8.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N;.;.;N;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D;.;.;D;.;.
Sift4G	Uncertain	0.020	D;.;.;D;T;D
Polyphen		0.99	D;.;.;D;.;.
Vest4		0.30
MutPred		0.078		Loss of MoRF binding (P = 0.134);Loss of MoRF binding (P = 0.134);Loss of MoRF binding (P = 0.134);Loss of MoRF binding (P = 0.134);Loss of MoRF binding (P = 0.134);Loss of MoRF binding (P = 0.134);
MVP		0.88
MPC		0.87
ClinPred		0.85	D
GERP RS		5.6
Varity_R		0.63
gMVP		0.41
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs756721244; hg19: chrX-18616729;