Genetic Variant NM_001323289.2:c.11C>G (chrX-18507107-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001323289.2(CDKL5):c.11C>G(p.Pro4Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Consequence

CDKL5
NM_001323289.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.95

Publications

0 publications found

Variant links:

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

CDKL5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKL5	NM_001323289.2	MANE Select	c.11C>G	p.Pro4Arg	missense	Exon 2 of 18	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2		c.11C>G	p.Pro4Arg	missense	Exon 3 of 22	NP_001032420.1	O76039-1
CDKL5	NM_003159.3		c.11C>G	p.Pro4Arg	missense	Exon 2 of 21	NP_003150.1	O76039-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.11C>G	p.Pro4Arg	missense	Exon 2 of 18	ENSP00000485244.1	O76039-2
CDKL5	ENST00000379989.6	TSL:1	c.11C>G	p.Pro4Arg	missense	Exon 3 of 22	ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7	TSL:1	c.11C>G	p.Pro4Arg	missense	Exon 2 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.067

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.9

PhyloP100

5.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.39

MutPred

0.45

Gain of MoRF binding (P = 1e-04)

MVP

0.86

MPC

2.5

ClinPred

0.92

GERP RS

5.4

Varity_R

0.39

gMVP

0.86

Mutation Taster

=39/61

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over