rs2296645

Positions:

• chr13-35828289-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001330071.2(DCLK1):​c.1248T>C​(p.Tyr416=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 1,605,488 control chromosomes in the GnomAD database, including 171,032 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.38 (12870 hom., cov: 32)
  • Exomes 𝑓: 0.46 (158162 hom.)
• Consequence: DCLK1 NM_001330071.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79

Genes affected

DCLK1 (HGNC:2700): (doublecortin like kinase 1) 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. The encoded protein is involved in several different cellular processes, including neuronal migration, retrograde transport, neuronal apoptosis and neurogenesis. This gene is up-regulated by brain-derived neurotrophic factor and associated with memory and general cognitive abilities. Multiple transcript variants generated by two alternative promoter usage and alternative splicing have been reported, but the full-length nature and biological validity of some variants have not been defined. These variants encode different isoforms, which are differentially expressed and have different kinase activities.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP7: Synonymous conserved (PhyloP=1.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCLK1	NM_001330071.2	c.1248T>C	p.Tyr416=	synonymous_variant	9/17	ENST00000360631.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCLK1	ENST00000360631.8	c.1248T>C	p.Tyr416=	synonymous_variant	9/17	5	NM_001330071.2	P3
DCLK1	ENST00000255448.8	c.1248T>C	p.Tyr416=	synonymous_variant	9/18	1		A1
DCLK1	ENST00000379893.5	c.327T>C	p.Tyr109=	synonymous_variant	5/13	2
DCLK1	ENST00000615680.5	c.327T>C	p.Tyr109=	synonymous_variant	5/14	2

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57665 AN: 151922 Hom.: 12868 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.428

GnomAD3 exomes AF: 0.436 AC: 107950 AN: 247372 Hom.: 25183 AF XY: 0.447 AC XY: 59904 AN XY: 133942

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.532

Gnomad EAS exome AF: 0.287

Gnomad SAS exome AF: 0.459

Gnomad FIN exome AF: 0.558

Gnomad NFE exome AF: 0.485

Gnomad OTH exome AF: 0.483

GnomAD4 exome AF: 0.461 AC: 669333 AN: 1453448 Hom.: 158162 Cov.: 33 AF XY: 0.463 AC XY: 335065 AN XY: 723314

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.378

Gnomad4 ASJ exome AF: 0.520

Gnomad4 EAS exome AF: 0.305

Gnomad4 SAS exome AF: 0.460

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.474

Gnomad4 OTH exome AF: 0.452

GnomAD4 genome AF: 0.379 AC: 57667 AN: 152040 Hom.: 12870 Cov.: 32 AF XY: 0.385 AC XY: 28625 AN XY: 74302

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.397

Gnomad4 ASJ AF: 0.530

Gnomad4 EAS AF: 0.291

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.575

Gnomad4 NFE AF: 0.479

Gnomad4 OTH AF: 0.432

Alfa AF: 0.468 Hom.: 13485

Bravo AF: 0.353

Asia WGS AF: 0.404 AC: 1405 AN: 3476

EpiCase AF: 0.487

EpiControl AF: 0.486

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.3
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2296645; hg19: chr13-36402426; COSMIC: COSV55172314;