chr10-73842486-C-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV001815757: "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".

• 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
• Publications: 9 publications found

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]

CAMK2G Gene-Disease associations (from GenCC):

• intellectual developmental disorder 59

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Illumina, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000229990 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001815757: "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
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 39975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367534.1. 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
	CAMK2G	NM_001367534.1	MANE Select	c.875G>C	p.Arg292Pro	missense	Exon 11 of 23	NP_001354463.1	H0Y6G2
	CAMK2G	NM_001320898.2		c.875G>C	p.Arg292Pro	missense	Exon 11 of 20	NP_001307827.1
	CAMK2G	NM_001367544.1		c.875G>C	p.Arg292Pro	missense	Exon 11 of 22	NP_001354473.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2G	ENST00000423381.6	TSL:5 MANE Select	c.875G>C	p.Arg292Pro	missense	Exon 11 of 23	ENSP00000410298.3	H0Y6G2
	CAMK2G	ENST00000322635.7	TSL:1	c.875G>C	p.Arg292Pro	missense	Exon 11 of 21	ENSP00000315599.3	Q13555-5
	CAMK2G	ENST00000433289.5	TSL:1	c.680G>C	p.Arg227Pro	missense	Exon 9 of 18	ENSP00000393784.1	Q8WU40

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual developmental disorder 59 (2)
1	-	-	Autism;C0036857:Severe intellectual disability;C0557874:Global developmental delay;C1858120:Generalized hypotonia (1)
1	-	-	Severe intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.79	P
Vest4		0.55
MutPred		0.52		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
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514627; hg19: chr10-75602244;