Variant chr19-53992881-A-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_145814.2(CACNG6):c.4A>T(p.Met2Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,396,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

CACNG6
NM_145814.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.86

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CACNG6	NM_145814.2 linkuse as main transcript	c.4A>T	p.Met2Leu	missense_variant	1/4	ENST00000252729.7	NP_665813.1
CACNG6	NM_145815.2 linkuse as main transcript	c.4A>T	p.Met2Leu	missense_variant	1/3		NP_665814.1
CACNG6	NM_031897.3 linkuse as main transcript	c.4A>T	p.Met2Leu	missense_variant	1/2		NP_114103.2
CACNG6	NR_102308.2 linkuse as main transcript	n.49+1684A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CACNG6	ENST00000252729.7 linkuse as main transcript	c.4A>T	p.Met2Leu	missense_variant	1/4	1	NM_145814.2	ENSP00000252729	P1
CACNG6	ENST00000346968.2 linkuse as main transcript	c.4A>T	p.Met2Leu	missense_variant	1/3	5		ENSP00000319097
CACNG6	ENST00000352529.1 linkuse as main transcript	c.4A>T	p.Met2Leu	missense_variant	1/2	5		ENSP00000319135

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.04e-7

AC:

AN:

1244010

Hom.:

Cov.:

AF XY:

0.00000165

AC XY:

AN XY:

606138

show subpopulations

Gnomad4 AFR exome

AF:

0.0000397

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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

May 09, 2022

The c.4A>T (p.M2L) alteration is located in exon 1 (coding exon 1) of the CACNG6 gene. This alteration results from a A to T substitution at nucleotide position 4, causing the methionine (M) at amino acid position 2 to be replaced by a leucine (L). 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

Uncertain

0.41

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.14

.;T;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.78

T;T;T

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.3

.;M;.

MutationTaster

Benign

0.87

D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.24

Sift

Pathogenic

0.0

D;D;D

Sift4G

Benign

0.062

T;T;T

Polyphen

0.80

P;P;P

Vest4

0.58

MutPred

0.28

Loss of MoRF binding (P = 0.1087);Loss of MoRF binding (P = 0.1087);Loss of MoRF binding (P = 0.1087);

MVP

0.41

MPC

1.3

ClinPred

0.96

GERP RS

3.1

Varity_R

0.86

gMVP

0.44

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