Genetic Variant CACNG5:p.Leu64Pro (chr17-66877523-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_145811.3(CACNG5):c.191T>C(p.Leu64Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CACNG5
NM_145811.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43

Variant links:

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]

CACNG5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNG5	NM_145811.3 link	c.191T>C	p.Leu64Pro	missense_variant	Exon 2 of 6	ENST00000533854.6	NP_665810.1	Q9UF02
CACNG5	NM_001371476.1 link	c.191T>C	p.Leu64Pro	missense_variant	Exon 2 of 5		NP_001358405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNG5	ENST00000533854.6 link	c.191T>C	p.Leu64Pro	missense_variant	Exon 2 of 6	2	NM_145811.3	ENSP00000436836.1	Q9UF02
CACNG5	ENST00000307139.4 link	c.191T>C	p.Leu64Pro	missense_variant	Exon 1 of 5	1		ENSP00000303092.3	Q9UF02
CACNG5	ENST00000673855.1 link	c.191T>C	p.Leu64Pro	missense_variant	Exon 1 of 4			ENSP00000501267.1	A0A669KBF6

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250174

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135194

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461368

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.191T>C (p.L64P) alteration is located in exon 1 (coding exon 1) of the CACNG5 gene. This alteration results from a T to C substitution at nucleotide position 191, causing the leucine (L) at amino acid position 64 to be replaced by a proline (P). 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

0.67

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

.;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.041

D;D

Polyphen

1.0

D;D

Vest4

0.80

MutPred

0.66

Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);

MVP

0.81

MPC

0.40

ClinPred

0.97

GERP RS

4.7

Varity_R

0.75

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over