NM_001367534.1:c.875G>C

Variant names:

• chr10-73842486-C-G
• rs397514627
• NM_001367534.1:c.875G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001367534.1(CAMK2G):​c.875G>C​(p.Arg292Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAMK2G NM_001367534.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.34

Genes affected

CAMK2G (HGNC:1463): (calcium/calmodulin dependent protein kinase II gamma) The product of this gene is one of the four subunits of an enzyme which belongs to the serine/threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. In mammalian cells the enzyme is composed of four different chains: alpha, beta, gamma, and delta. The product of this gene is a gamma chain. Many alternatively spliced transcripts encoding different isoforms have been described but the full-length nature of all the variants has not been determined.[provided by RefSeq, Mar 2011]

ENSG00000229990 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-73842486-C-G is Pathogenic according to our data. Variant chr10-73842486-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-73842486-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAMK2G	NM_001367534.1	c.875G>C	p.Arg292Pro	missense_variant	Exon 11 of 23	ENST00000423381.6	NP_001354463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMK2G	ENST00000423381.6	c.875G>C	p.Arg292Pro	missense_variant	Exon 11 of 23	5	NM_001367534.1	ENSP00000410298.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder 59 Pathogenic:2

Oct 02, 2020

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The de novo heterozygous p.Arg292Pro missense variant identified in the CAMK2G gene has been reported in at least two unrelated patients affected with a neurological disorder [PMID: 23033978; PMID: 28191890; PMID: 30184290]. The variant has been reported as likely pathogenic in the ClinVar database [variation ID:39975]. The variant is absent from gnomAD(v3) database suggesting it is an extremely rare allele in the populations represented in this database. In vivoand in vitro functional analysis showed that the p.Arg292Pro variant exerts it’s pathogenic effect through gain-of-function mechanism via increased phosphotransferase activity, impaired neuronal maturation and impaired targeting of nuclear isoform [PMID: 30184290]. Based on the available evidence, the de novo p.Arg292Pro missense variant identified in the CAMK2G gene is reported here as Pathogenic. -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Autism;C0036857:Intellectual disability, severe;C0557874:Global developmental delay;C1858120:Generalized hypotonia Pathogenic:1

Sep 21, 2016

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Parental studies indicated that this alteration is de novo in this individual. This alteration has been previously reported in the Human Gene Mutation Database and is associated with sporadic global developmental delay, hypotonia, and speech delay (GeneMatcher communication and de Ligt et al. (2012) N. Engl. J. Med. 367(20):1921-1929). This variant is not listed in the public SNP databases (ExAC, gnomAD) and is predicted to be deleterious or possibly damaging by multiple in silico algorithms (LRT, SIFT, PROVEAN, PolyPhen2-HumDiv). Based on the ACMG Guidelines for variant interpretation, using the criteria PS2, PS4 (downgraded to moderate), PM2, and PP3, this variant is classified as likely pathogenic. -

Intellectual disability, severe Pathogenic:1

Nov 15, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;.;.;.;D;.;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.5	L;L;L;.;L;.;L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		0.79	P;B;.;.;P;.;B;.
Vest4		0.55
MutPred		0.52		Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);.;Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);
MVP		0.80
MPC		2.8
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.90

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: rs397514627; hg19: chr10-75602244;