Variant 19-53999699-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_145814.2(CACNG6):c.472T>C(p.Cys158Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,732 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C158Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

CACNG6
NM_145814.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.91

Variant links:

Genes affected

CACNG6 (HGNC:13625): (calcium voltage-gated channel auxiliary subunit gamma 6) Voltage-dependent calcium channels are composed of five subunits. The protein encoded by this gene represents one of these subunits, gamma, and is one of two known gamma subunit proteins. This particular gamma subunit is an integral membrane protein that is thought to stabilize the calcium channel in an inactive (closed) state. 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 that function as transmembrane AMPA receptor regulatory proteins (TARPs). Alternative splicing results in multiple transcript variants. Variants in this gene have been associated with aspirin-intolerant asthma. [provided by RefSeq, Dec 2010]

CACNG6 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, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CACNG6	NM_145814.2 linkuse as main transcript	c.472T>C	p.Cys158Arg	missense_variant	3/4	ENST00000252729.7
CACNG6	NM_031897.3 linkuse as main transcript	c.331+6491T>C		intron_variant
CACNG6	NM_145815.2 linkuse as main transcript	c.406+1386T>C		intron_variant
CACNG6	NR_102308.2 linkuse as main transcript	n.124+1386T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CACNG6	ENST00000252729.7 linkuse as main transcript	c.472T>C	p.Cys158Arg	missense_variant	3/4	1	NM_145814.2	P1
CACNG6	ENST00000346968.2 linkuse as main transcript	c.406+1386T>C		intron_variant		5
CACNG6	ENST00000352529.1 linkuse as main transcript	c.331+6491T>C		intron_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251330

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135834

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:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.472T>C (p.C158R) alteration is located in exon 3 (coding exon 3) of the CACNG6 gene. This alteration results from a T to C substitution at nucleotide position 472, causing the cysteine (C) at amino acid position 158 to be replaced by an arginine (R). 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

0.96

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.63

M_CAP

Benign

0.084

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-8.5

REVEL

Uncertain

0.44

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.78

Vest4

0.91

MutPred

0.69

Gain of MoRF binding (P = 0.056);

MVP

0.85

MPC

1.8

ClinPred

0.97

GERP RS

3.9

Varity_R

0.93

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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