14-50345042-C-T

Variant names:

• chr14-50345042-C-T
• rs764133695
• NM_004196.7:c.307G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004196.7(CDKL1):​c.307G>A​(p.Val103Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: CDKL1 NM_004196.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24344224).

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.307G>A	p.Val103Met	missense	Exon 4 of 10	NP_004187.3
	CDKL1	NM_001423761.1		c.307G>A	p.Val103Met	missense	Exon 3 of 9	NP_001410690.1	Q00532-1
	CDKL1	NM_001423762.1		c.307G>A	p.Val103Met	missense	Exon 4 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.307G>A	p.Val103Met	missense	Exon 4 of 10	ENSP00000379176.2	A0A9S7JKS7
	CDKL1	ENST00000216378.2	TSL:1	c.310G>A	p.Val104Met	missense	Exon 4 of 9	ENSP00000216378.2	A0A5H1ZRP5
	CDKL1	ENST00000356146.5	TSL:1	n.2227-1984G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 251094 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461688 Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17 AN XY: 727154

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39684

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86234

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111916

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

African (AFR) AF: 0.0000483 AC: 2 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000384 AC: 2 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.61	T
PhyloP100		2.9
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.28
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.012	D
Vest4		0.39
MVP		0.22
MPC		0.30
ClinPred		0.33	T
GERP RS		4.6
gMVP		0.65
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs764133695; hg19: chr14-50811760;