Genetic Variant DCLK3:p.His804Tyr (chr3-36715372-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394672.2(DCLK3):c.2410C>T(p.His804Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000795 in 1,614,032 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00082 ( 1 hom. )

Consequence

DCLK3
NM_001394672.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.02

Variant links:

Genes affected

DCLK3 (HGNC:19005): (doublecortin like kinase 3) Predicted to enable protein kinase activity. Predicted to be involved in peptidyl-serine phosphorylation. Predicted to act upstream of or within negative regulation of protein localization to nucleus. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

DCLK3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13850608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCLK3	NM_001394672.2 link	c.2410C>T	p.His804Tyr	missense_variant	Exon 5 of 5	ENST00000636136.2	NP_001381601.1
DCLK3	NM_033403.1 link	c.1903C>T	p.His635Tyr	missense_variant	Exon 5 of 5		NP_208382.1	Q9C098B3KVM3
DCLK3	XM_047449090.1 link	c.2242C>T	p.His748Tyr	missense_variant	Exon 4 of 4		XP_047305046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCLK3	ENST00000636136.2 link	c.2410C>T	p.His804Tyr	missense_variant	Exon 5 of 5	5	NM_001394672.2	ENSP00000489900.1		A0A1B0GTZ4
DCLK3	ENST00000416516.2 link	c.1903C>T	p.His635Tyr	missense_variant	Exon 5 of 5	5		ENSP00000394484.2		Q9C098

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00106

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000349

AC:

AN:

249282

Hom.:

AF XY:

0.000458

AC XY:

AN XY:

135254

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000699

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000821

AC:

1200

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000811

AC XY:

590

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.000545

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000618

Hom.:

Bravo

AF:

0.000461

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000727

AC:

ESP6500EA

AF:

0.00119

AC:

ExAC

AF:

0.000355

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1903C>T (p.H635Y) alteration is located in exon 5 (coding exon 4) of the DCLK3 gene. This alteration results from a C to T substitution at nucleotide position 1903, causing the histidine (H) at amino acid position 635 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.0

M;.

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.2

D;.

REVEL

Benign

0.21

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0060

D;.

Polyphen

0.93

P;.

Vest4

0.23

MVP

0.87

MPC

0.44

ClinPred

0.17

GERP RS

4.9

Varity_R

0.40

gMVP

0.48

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over