NM_001744.6:c.304A>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/24 in silico tools predict a benign 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: 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
• Publications: 0 publications found

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]

CAMK4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001744.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK4	NM_001744.6	MANE Select	c.304A>G	p.Ile102Val	missense splice_region	Exon 4 of 11	NP_001735.1	Q16566
	CAMK4	NM_001323374.2		c.304A>G	p.Ile102Val	missense splice_region	Exon 5 of 12	NP_001310303.1	Q16566
	CAMK4	NM_001323375.2		c.304A>G	p.Ile102Val	missense splice_region	Exon 5 of 12	NP_001310304.1	Q16566

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK4	ENST00000282356.9	TSL:1 MANE Select	c.304A>G	p.Ile102Val	missense splice_region	Exon 4 of 11	ENSP00000282356.4	Q16566
	CAMK4	ENST00000512453.5	TSL:1	c.304A>G	p.Ile102Val	missense splice_region	Exon 5 of 12	ENSP00000422634.1	Q16566
	CAMK4	ENST00000515231.5	TSL:1	n.241-17850A>G		intron	N/A	ENSP00000424912.1	D6RCD6

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31902

American (AMR) AF: 0.00 AC: 0 AN: 42562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25340

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39046

South Asian (SAS) AF: 0.00 AC: 0 AN: 82456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00000281 AC: 3 AN: 1066410

Other (OTH) AF: 0.00 AC: 0 AN: 58286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0404278), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.034
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.53	N
PhyloP100		7.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.20
Sift	Benign	0.85	T
Sift4G	Benign	0.64	T
Polyphen		0.042	B
Vest4		0.47
MutPred		0.46		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
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs928027119; hg19: chr5-110712558;