5-111376860-A-G

Variant names:

• chr5-111376860-A-G
• rs928027119
• NM_001744.6:c.304A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001744.6(CAMK4):​c.304A>G​(p.Ile102Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,404,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CAMK4 NM_001744.6 missense, splice_region
• Scores: Splicing: ADA: 0.0005995
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26570994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAMK4	NM_001744.6	c.304A>G	p.Ile102Val	missense_variant, splice_region_variant	Exon 4 of 11	ENST00000282356.9	NP_001735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMK4	ENST00000282356.9	c.304A>G	p.Ile102Val	missense_variant, splice_region_variant	Exon 4 of 11	1	NM_001744.6	ENSP00000282356.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1404730 Hom.: 0 Cov.: 22 AF XY: 0.00000285 AC XY: 2 AN XY: 701536

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000281

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.304A>G (p.I102V) alteration is located in exon 4 (coding exon 4) of the CAMK4 gene. This alteration results from a A to G substitution at nucleotide position 304, causing the isoleucine (I) at amino acid position 102 to be replaced by a valine (V). 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	Uncertain	0.48
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Benign	0.76
DEOGEN2	Benign	0.0099	T;T;T
Eigen	Benign	-0.034
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.53	.;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.48	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.85	T;T;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.042	.;B;B
Vest4		0.47
MutPred		0.46		Gain of methylation at K103 (P = 0.0576);Gain of methylation at K103 (P = 0.0576);Gain of methylation at K103 (P = 0.0576);
MVP		0.64
MPC		0.67
ClinPred		0.54	D
GERP RS		5.8
Varity_R		0.40
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00060
dbscSNV1_RF	Benign	0.016
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: rs928027119; hg19: chr5-110712558;