14-50395790-C-A

Variant names:

• chr14-50395790-C-A
• rs762672174
• NM_004196.7:c.79G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004196.7(CDKL1):​c.79G>T​(p.Gly27Cys) 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 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. G27S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKL1 NM_004196.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.81
• Publications: 0 publications found

Genes affected

CDKL1 (HGNC:1781): (cyclin dependent kinase like 1) This gene product is a member of a large family of CDC2-related serine/threonine protein kinases that accumulates primarily in the nucleus. [provided by RefSeq, Nov 2018]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004196.7. 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
	CDKL1	NM_004196.7	MANE Select	c.79G>T	p.Gly27Cys	missense	Exon 2 of 10	NP_004187.3
	CDKL1	NM_001423761.1		c.79G>T	p.Gly27Cys	missense	Exon 1 of 9	NP_001410690.1	Q00532-1
	CDKL1	NM_001423762.1		c.79G>T	p.Gly27Cys	missense	Exon 2 of 10	NP_001410691.1	A0A9S7JKS7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL1	ENST00000395834.6	TSL:1 MANE Select	c.79G>T	p.Gly27Cys	missense	Exon 2 of 10	ENSP00000379176.2	A0A9S7JKS7
	CDKL1	ENST00000216378.2	TSL:1	c.82G>T	p.Gly28Cys	missense	Exon 2 of 9	ENSP00000216378.2	A0A5H1ZRP5
	CDKL1	ENST00000356146.5	TSL:1	n.649G>T		non_coding_transcript_exon	Exon 5 of 20

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251458 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.093	D
PhyloP100		7.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.87
MVP		0.88
MPC		0.93
ClinPred		1.0	D
GERP RS		4.3
gMVP		0.63
Mutation Taster		=16/84	disease causing

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: rs762672174; hg19: chr14-50862508;