22-36564875-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006078.5(CACNG2):c.448A>G(p.Ile150Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNG2 NM_006078.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

CACNG2 (HGNC:1406): (calcium voltage-gated channel auxiliary subunit gamma 2) The protein encoded by this gene is a type I transmembrane AMPA receptor regulatory protein (TARP). TARPs regulate both trafficking and channel gating of the AMPA receptors. The AMPA subtype of ionotropic glutamate receptors are ligand gated ion channels that are typically activated by glutamate released from presynaptic neuron terminals and mediate fast neurotransmission in excitatory synapses. TARPs thus play an important role in synaptic plasticity, learning and memory. Mutations in this gene cause an autosomal dominant form of cognitive disability. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNG2	NM_006078.5	c.448A>G	p.Ile150Val	missense_variant	4/4	ENST00000300105.7
CACNG2	NM_001379051.1	c.379A>G	p.Ile127Val	missense_variant	5/5
CACNG2	XM_017028531.3	c.190A>G	p.Ile64Val	missense_variant	3/3
CACNG2	NR_166440.1	n.1814A>G		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNG2	ENST00000300105.7	c.448A>G	p.Ile150Val	missense_variant	4/4	1	NM_006078.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2022

The c.448A>G (p.I150V) alteration is located in exon 4 (coding exon 4) of the CACNG2 gene. This alteration results from a A to G substitution at nucleotide position 448, causing the isoleucine (I) at amino acid position 150 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.83	N
REVEL	Pathogenic	0.67
Sift	Benign	0.46	T
Sift4G	Benign	0.19	T
Polyphen		0.70	P
Vest4		0.64
MutPred		0.62		Gain of sheet (P = 0.1208);
MVP		0.70
MPC		1.8
ClinPred		0.90	D
GERP RS		5.5
Varity_R		0.38
gMVP		0.88

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: rs1935100374; hg19: chr22-36960922;