NM_015981.4:c.1429C>T

Variant names:

• chr5-150223026-G-A
• rs1554119274
• NM_015981.4:c.1429C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_015981.4(CAMK2A):​c.1429C>T​(p.His477Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAMK2A NM_015981.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.60
• Publications: 4 publications found

Genes affected

CAMK2A (HGNC:1460): (calcium/calmodulin dependent protein kinase II alpha) The product of this gene belongs to the serine/threonine protein kinases family, and to the Ca(2+)/calmodulin-dependent protein kinases subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. This calcium calmodulin-dependent protein kinase is composed of four different chains: alpha, beta, gamma, and delta. The alpha chain encoded by this gene is required for hippocampal long-term potentiation (LTP) and spatial learning. In addition to its calcium-calmodulin (CaM)-dependent activity, this protein can undergo autophosphorylation, resulting in CaM-independent activity. Several transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2018]

SLC6A7 (HGNC:11054): (solute carrier family 6 member 7) This gene is a member of the gamma-aminobutyric acid (GABA) neurotransmitter gene family and encodes a high-affinity mammalian brain L-proline transporter protein. This transporter protein differs from other sodium-dependent plasma membrane carriers by its pharmacological specificity, kinetic properties, and ionic requirements. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 5-150223026-G-A is Pathogenic according to our data. Variant chr5-150223026-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 560170.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015981.4. 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
	CAMK2A	NM_015981.4	MANE Select	c.1429C>T	p.His477Tyr	missense	Exon 18 of 19	NP_057065.2
	CAMK2A	NM_001363989.1		c.1429C>T	p.His477Tyr	missense	Exon 19 of 20	NP_001350918.1	Q9UQM7-2
	CAMK2A	NM_001363990.1		c.1396C>T	p.His466Tyr	missense	Exon 18 of 19	NP_001350919.1	Q7LDD5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2A	ENST00000671881.1	MANE Select	c.1429C>T	p.His477Tyr	missense	Exon 18 of 19	ENSP00000500386.1	Q9UQM7-2
	CAMK2A	ENST00000348628.11	TSL:1	c.1396C>T	p.His466Tyr	missense	Exon 17 of 18	ENSP00000261793.8	Q9UQM7-1
	CAMK2A	ENST00000398376.8	TSL:1	c.1225C>T	p.His409Tyr	missense	Exon 15 of 16	ENSP00000381412.4	A0A5K1VW76

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, autosomal recessive 63 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.84		Gain of sheet (P = 0.0477)
MVP		0.73
MPC		2.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.92
Mutation Taster		=16/84	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: rs1554119274; hg19: chr5-149602589; COSMIC: COSV104539172; COSMIC: COSV104539172;