17-66885220-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145811.3(CACNG5):c.808A>G(p.Met270Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,443,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNG5 NM_145811.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

Genes affected

CACNG5 (HGNC:1409): (calcium voltage-gated channel auxiliary subunit gamma 5) The protein encoded by this gene is a type II transmembrane AMPA receptor regulatory protein (TARP). TARPs regulate both trafficking and channel gating of the AMPA receptors. This gene is part of a functionally diverse eight-member protein subfamily of the PMP-22/EMP/MP20 family and is located in a cluster with two family members, a type I TARP and a calcium channel gamma subunit. This gene is a susceptibility locus for schizophrenia and bipolar disorder. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07379216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNG5	NM_145811.3	c.808A>G	p.Met270Val	missense_variant	6/6	ENST00000533854.6
CACNG5	NM_001371476.1	c.424+4523A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNG5	ENST00000533854.6	c.808A>G	p.Met270Val	missense_variant	6/6	2	NM_145811.3	P1
CACNG5	ENST00000307139.4	c.808A>G	p.Met270Val	missense_variant	5/5	1		P1
CACNG5	ENST00000673855.1	c.424+4523A>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443610 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 717632

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jul 12, 2022

The c.808A>G (p.M270V) alteration is located in exon 5 (coding exon 5) of the CACNG5 gene. This alteration results from a A to G substitution at nucleotide position 808, causing the methionine (M) at amino acid position 270 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	Benign	0.063
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Benign	0.87
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N;N
MutationTaster	Benign	0.57	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.74	N;N
REVEL	Benign	0.16
Sift	Benign	0.46	T;T
Sift4G	Benign	0.74	T;T
Polyphen		0.0	B;B
Vest4		0.26
MutPred		0.12		Gain of glycosylation at S273 (P = 0.0831);Gain of glycosylation at S273 (P = 0.0831);
MVP		0.20
MPC		0.22
ClinPred		0.083	T
GERP RS		2.2
Varity_R		0.095
gMVP		0.39

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: rs772229838; hg19: chr17-64881337;