19-53993139-A-G

Position:

chr19-53993139-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145814.2(CACNG6):c.262A>G(p.Thr88Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,548,154 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: 𝑓 0.00074 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

CACNG6
NM_145814.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0200

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.017474025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CACNG6	NM_145814.2 linkuse as main transcript	c.262A>G	p.Thr88Ala	missense_variant	1/4	ENST00000252729.7
CACNG6	NM_145815.2 linkuse as main transcript	c.262A>G	p.Thr88Ala	missense_variant	1/3
CACNG6	NM_031897.3 linkuse as main transcript	c.262A>G	p.Thr88Ala	missense_variant	1/2
CACNG6	NR_102308.2 linkuse as main transcript	n.49+1942A>G		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.262A>G	p.Thr88Ala	missense_variant	1/4	1	NM_145814.2	P1
CACNG6	ENST00000346968.2 linkuse as main transcript	c.262A>G	p.Thr88Ala	missense_variant	1/3	5
CACNG6	ENST00000352529.1 linkuse as main transcript	c.262A>G	p.Thr88Ala	missense_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

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:

0.000956

GnomAD3 exomes

AF:

0.000150

AC:

AN:

140264

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

75436

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.0000820

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:

0.00

Gnomad OTH exome

AF:

0.000243

GnomAD4 exome

AF:

0.0000544

AC:

AN:

1395898

Hom.:

Cov.:

AF XY:

0.0000465

AC XY:

AN XY:

688650

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.000112

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:

0.000138

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152256

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.000785

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:

0.000946

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000767

ESP6500AA

AF:

0.00132

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000703

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

Dec 12, 2023

The c.262A>G (p.T88A) alteration is located in exon 1 (coding exon 1) of the CACNG6 gene. This alteration results from a A to G substitution at nucleotide position 262, causing the threonine (T) at amino acid position 88 to be replaced by an alanine (A). 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

0.084

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.098

.;T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.58

T;T;T

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.4

.;L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.030

Sift

Benign

0.080

T;T;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.028

MVP

0.65

MPC

0.47

ClinPred

0.0071

GERP RS

1.5

Varity_R

0.071

gMVP

0.46

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