Genetic Variant CACNG6:p.Pro105Ser (chr19-53993190-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_145814.2(CACNG6):c.313C>T(p.Pro105Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,389,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P105L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNG6
NM_145814.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.16

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 rank	MANE	Protein	UniProt
CACNG6	NM_145814.2 link	c.313C>T	p.Pro105Ser	missense_variant	Exon 1 of 4	ENST00000252729.7	NP_665813.1	Q9BXT2
CACNG6	NM_145815.2 link	c.313C>T	p.Pro105Ser	missense_variant	Exon 1 of 3		NP_665814.1	Q9BXT2A6NFR2
CACNG6	NM_031897.3 link	c.313C>T	p.Pro105Ser	missense_variant	Exon 1 of 2		NP_114103.2	Q9BXT2A6NP74
CACNG6	NR_102308.2 link	n.49+1993C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNG6	ENST00000252729.7 link	c.313C>T	p.Pro105Ser	missense_variant	Exon 1 of 4	1	NM_145814.2	ENSP00000252729.2	Q9BXT2
CACNG6	ENST00000346968.2 link	c.313C>T	p.Pro105Ser	missense_variant	Exon 1 of 3	5		ENSP00000319097.2	A6NFR2
CACNG6	ENST00000352529.1 link	c.313C>T	p.Pro105Ser	missense_variant	Exon 1 of 2	5		ENSP00000319135.1	A6NP74

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000152

AC:

AN:

131370

Hom.:

AF XY:

0.0000139

AC XY:

AN XY:

71714

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000192

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1389414

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

685572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000561

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.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313C>T (p.P105S) alteration is located in exon 1 (coding exon 1) of the CACNG6 gene. This alteration results from a C to T substitution at nucleotide position 313, causing the proline (P) at amino acid position 105 to be replaced by a serine (S). 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

0.85

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;T;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Uncertain

0.62

D;D;D

MetaSVM

Uncertain

-0.27

MutationAssessor

Uncertain

2.6

.;M;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.0

D;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.013

D;D;D

Sift4G

Uncertain

0.028

D;D;D

Polyphen

1.0

D;B;B

Vest4

0.59

MutPred

0.41

Loss of glycosylation at T102 (P = 0.0462);Loss of glycosylation at T102 (P = 0.0462);Loss of glycosylation at T102 (P = 0.0462);

MVP

0.84

MPC

0.60

ClinPred

0.94

GERP RS

2.5

Varity_R

0.36

gMVP

0.73

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