rs1215770918

Variant names:

• chr4-75607355-G-A
• rs1215770918
• NM_001330724.2:c.370C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-75607355-G-A
• chr4-75607355-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001330724.2(CDKL2):​c.370C>T​(p.His124Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. H124D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDKL2 NM_001330724.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.61

Genes affected

CDKL2 (HGNC:1782): (cyclin dependent kinase like 2) This gene product is a member of a large family of CDC2-related serine/threonine protein kinases. It accumulates primarily in the cytoplasm, with lower levels in the nucleus. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL2	NM_001330724.2	c.370C>T	p.His124Tyr	missense_variant	Exon 4 of 14	ENST00000307465.9	NP_001317653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL2	ENST00000307465.9	c.370C>T	p.His124Tyr	missense_variant	Exon 4 of 14	2	NM_001330724.2	ENSP00000306340.4
CDKL2	ENST00000429927.6	c.370C>T	p.His124Tyr	missense_variant	Exon 4 of 12	1		ENSP00000412365.2
CDKL2	ENST00000506234.1	n.169-3399C>T		intron_variant	Intron 2 of 4	2		ENSP00000422666.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459424 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726074

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110434

Other (OTH) AF: 0.00 AC: 0 AN: 60288

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		8.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.91		Gain of catalytic residue at H124 (P = 0.0188);Gain of catalytic residue at H124 (P = 0.0188);
MVP		0.93
MPC		0.15
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.93
gMVP		0.90
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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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Other links and lift over

dbSNP: rs1215770918; hg19: chr4-76532539;