rs397514627

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-73842486-C-A
• chr10-73842486-C-G
• chr10-73842486-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001367534.1(CAMK2G):​c.875G>T​(p.Arg292Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,446 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R292P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAMK2G NM_001367534.1 missense
• Clinical Significance: Not reported in ClinVar
• 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: G2P, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, ClinGen
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000229990 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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>T	p.Arg292Leu	missense	Exon 11 of 23	NP_001354463.1
	CAMK2G	NM_001320898.2		c.875G>T	p.Arg292Leu	missense	Exon 11 of 20	NP_001307827.1
	CAMK2G	NM_001367544.1		c.875G>T	p.Arg292Leu	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>T	p.Arg292Leu	missense	Exon 11 of 23	ENSP00000410298.3
	CAMK2G	ENST00000322635.7	TSL:1	c.875G>T	p.Arg292Leu	missense	Exon 11 of 21	ENSP00000315599.3
	CAMK2G	ENST00000433289.5	TSL:1	c.680G>T	p.Arg227Leu	missense	Exon 9 of 18	ENSP00000393784.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251460 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461446 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727072

⚠️ 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: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111608

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.14	B
Vest4		0.50
MutPred		0.52		Loss of MoRF binding (P = 0.0302)
MVP		0.82
MPC		2.0
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.73
gMVP		0.78
Mutation Taster		=5/95	disease causing

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;