4-150221780-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001040260.4(DCLK2):c.1236A>G(p.Ile412Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000032 in 1,563,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: DCLK2 NM_001040260.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.845

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03360343).
• BP6: Variant 4-150221780-A-G is Benign according to our data. Variant chr4-150221780-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2523783.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCLK2	NM_001040260.4	c.1236A>G	p.Ile412Met	missense_variant	7/16	ENST00000296550.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCLK2	ENST00000296550.12	c.1236A>G	p.Ile412Met	missense_variant	7/16	1	NM_001040260.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 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: 0.000770

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

GnomAD3 exomes AF: 0.0000606 AC: 14 AN: 231018 Hom.: 0 AF XY: 0.0000558 AC XY: 7 AN XY: 125400

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000843

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000326 AC: 46 AN: 1411420 Hom.: 0 Cov.: 25 AF XY: 0.0000299 AC XY: 21 AN XY: 703176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000512

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.00116 AC: 4 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	13
Dann	Benign	0.91
DEOGEN2	Benign	0.035	T;T;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	L;.;.;.
MutationTaster	Benign	0.59	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.80	N;.;N;N
REVEL	Benign	0.070
Sift	Benign	0.24	T;.;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.0030	B;.;B;B
Vest4		0.11
MutPred		0.44		Gain of catalytic residue at V408 (P = 0.0116);.;.;.;
MVP		0.33
MPC		0.82
ClinPred		0.041	T
GERP RS		4.2
Varity_R		0.17
gMVP		0.39

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

Other links and lift over

dbSNP: rs534744184; hg19: chr4-151142932;