5-111482896-C-T

Position:

• chr5-111482896-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001744.6(CAMK4):​c.940C>T​(p.Gln314Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAMK4 NM_001744.6 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.49

Genes affected

CAMK4 (HGNC:1464): (calcium/calmodulin dependent protein kinase IV) The product of this gene belongs to the serine/threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. This enzyme is a multifunctional serine/threonine protein kinase with limited tissue distribution, that has been implicated in transcriptional regulation in lymphocytes, neurons and male germ cells. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMK4	NM_001744.6	c.940C>T	p.Gln314Ter	stop_gained	10/11	ENST00000282356.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMK4	ENST00000282356.9	c.940C>T	p.Gln314Ter	stop_gained	10/11	1	NM_001744.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 12, 2020

Variant summary: CAMK4 c.940C>T (p.Gln314X) results in a premature termination codon, though this variant is not expected to elicit nonsense mediated decay (NMD), it is predicted to cause a truncation of the encoded protein, resulting in the partial loss of the autoregulatory domain (residues 305-341) at the carboxyl terminus (Zech_2018). The variant was absent in 249106 control chromosomes (gnomAD). The variant, c.940C>T, has not been reported in the literature in individuals affected with CAMK4-Related Disorders, however a variant resulting in loss of the carboxy-terminal regulatory domain (i.e. c.981+1G>A, p.Lys303Serfs28) has been reported as a de novo variant in a patient with neurodevelopmental disorders (impaired intellectual development, autistic features) and hyperkinetic movement conditions (including dystonia, myoclonus, and choreoathetosis) that grew progressively worse during adolescence (Zech_2018). This publication also reported experimental evidence evaluating an impact on protein function, where analysis of patient derived fibroblasts showed that the variant mRNA was not subject to NMD, and the expressed protein had increased kinase activity toward a downstream substrate (Zech_2018). These data are consistent with earlier studies that demonstrated a gain of function mechanism, resulting in a constitutively active protein, for in vitro expressed proteins lacking the C-terminal regulatory domain (Anderson_2004). However, these data do not provide unequivocal conclusions about association of the variant c.940C>T (p.Gln314X) with CAMK4-Related Disorders. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 23, 2020

The CAMK4 c.940C>T (p.Gln314Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein, including loss of the autoinhibitory domain (AID) and the calmodulin-binding domain (CBD). The variant is located in the penultimate exon of the gene, and the truncated transcript is not expected to undergo nonsense mediated decay. This variant has been reported in one study in the literature (Zech et al. 2021). This variant is not found in the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggests that the variant is rare. Cruzalegui et al. (1993) used insect cells to show that truncation of CAMKIV via introduction of the p.Gln314Ter variant resulted in a constitutively active kinase that did not bind calmodulin or undergo autophosphorylation in a calcium-dependent manner. Based on the available evidence, the p.Gln314Ter variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D
Vest4		0.95
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1755482400; hg19: chr5-110818594;