5-111224643-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001744.6(CAMK4):c.160C>T(p.Arg54Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000689 in 1,451,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CAMK4 NM_001744.6 missense, splice_region
• Scores: Splicing: ADA: 0.8752
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAMK4	NM_001744.6	c.160C>T	p.Arg54Trp	missense_variant, splice_region_variant	1/11	ENST00000282356.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAMK4	ENST00000282356.9	c.160C>T	p.Arg54Trp	missense_variant, splice_region_variant	1/11	1	NM_001744.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451592 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721590

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.160C>T (p.R54W) alteration is located in exon 1 (coding exon 1) of the CAMK4 gene. This alteration results from a C to T substitution at nucleotide position 160, causing the arginine (R) at amino acid position 54 to be replaced by a tryptophan (W). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D;.;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.025	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.35	.;B;B
Vest4		0.68, 0.59
MutPred		0.61		Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);
MVP		0.80
MPC		1.1
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.87
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.040		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: rs1748087413; hg19: chr5-110560341;