NM_001040260.4:c.297C>A

Variant names:

• chr4-150079324-C-A
• rs61744627
• NM_001040260.4:c.297C>A

Variant summary

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

The NM_001040260.4(DCLK2):​c.297C>A​(p.Phe99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,437,438 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DCLK2 NM_001040260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.669
• Publications: 1 publications found

Genes affected

DCLK2 (HGNC:19002): (doublecortin like kinase 2) This gene encodes a member of the protein kinase superfamily and the doublecortin family. The protein encoded by this gene contains two N-terminal doublecortin domains, which bind microtubules and regulate microtubule polymerization, a C-terminal serine/threonine protein kinase domain, which shows substantial homology to Ca2+/calmodulin-dependent protein kinase, and a serine/proline-rich domain in between the doublecortin and the protein kinase domains, which mediates multiple protein-protein interactions. The microtubule-polymerizing activity of the encoded protein is independent of its protein kinase activity. Mouse studies show that the DCX gene, another family member, and this gene share function in the establishment of hippocampal organization and that their absence results in a severe epileptic phenotype and lethality, as described in human patients with lissencephaly. Multiple alternatively spliced transcript variants have been identified. [provided by RefSeq, Sep 2010]

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=0.36694613).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040260.4. 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
	DCLK2	NM_001040260.4	MANE Select	c.297C>A	p.Phe99Leu	missense	Exon 1 of 16	NP_001035350.2	Q8N568-1
	DCLK2	NM_001040261.5		c.297C>A	p.Phe99Leu	missense	Exon 1 of 17	NP_001035351.4	Q8N568-3
	DCLK2	NM_001410852.1		c.297C>A	p.Phe99Leu	missense	Exon 1 of 16	NP_001397781.1	Q8N568-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLK2	ENST00000296550.12	TSL:1 MANE Select	c.297C>A	p.Phe99Leu	missense	Exon 1 of 16	ENSP00000296550.7	Q8N568-1
	DCLK2	ENST00000302176.8	TSL:1	c.297C>A	p.Phe99Leu	missense	Exon 1 of 17	ENSP00000303887.8	Q8N568-3
	DCLK2	ENST00000411937.6	TSL:1	n.297C>A		non_coding_transcript_exon	Exon 1 of 17	ENSP00000401916.2	G5E9L9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1437438 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712940

African (AFR) AF: 0.00 AC: 0 AN: 32782

American (AMR) AF: 0.00 AC: 0 AN: 41256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25662

East Asian (EAS) AF: 0.00 AC: 0 AN: 38014

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100264

Other (OTH) AF: 0.00 AC: 0 AN: 59518

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.3	L
PhyloP100		0.67
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.39
Sift	Benign	0.059	T
Sift4G	Benign	0.077	T
Polyphen		0.024	B
Vest4		0.11
MutPred		0.90		Gain of phosphorylation at S98 (P = 0.2465)
MVP		0.77
MPC		0.31
ClinPred		0.80	D
GERP RS		2.5
PromoterAI		-0.020	Neutral
Varity_R		0.39
gMVP		0.66
Mutation Taster		=58/42	polymorphism

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: rs61744627; hg19: chr4-151000476;