chr4-150079173-C-A

Variant names:

• chr4-150079173-C-A
• rs1349055211
• NM_001040260.4:c.146C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001040260.4(DCLK2):​c.146C>A​(p.Ala49Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,608,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DCLK2 NM_001040260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37590843).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.146C>A	p.Ala49Glu	missense	Exon 1 of 16	NP_001035350.2	Q8N568-1
	DCLK2	NM_001040261.5		c.146C>A	p.Ala49Glu	missense	Exon 1 of 17	NP_001035351.4	Q8N568-3
	DCLK2	NM_001410852.1		c.146C>A	p.Ala49Glu	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.146C>A	p.Ala49Glu	missense	Exon 1 of 16	ENSP00000296550.7	Q8N568-1
	DCLK2	ENST00000302176.8	TSL:1	c.146C>A	p.Ala49Glu	missense	Exon 1 of 17	ENSP00000303887.8	Q8N568-3
	DCLK2	ENST00000411937.6	TSL:1	n.146C>A		non_coding_transcript_exon	Exon 1 of 17	ENSP00000401916.2	G5E9L9

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1456756 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724416

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25718

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 85382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109654

Other (OTH) AF: 0.00 AC: 0 AN: 60136

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.27
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.67
MutPred		0.22		Loss of sheet (P = 0.0228)
MVP		0.79
MPC		0.98
ClinPred		0.97	D
GERP RS		4.5
PromoterAI		0.038	Neutral
Varity_R		0.50
gMVP		0.75
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: rs1349055211; hg19: chr4-151000325;