19-54011984-G-T

Variant names:

• chr19-54011984-G-T
• rs139947484
• NM_145814.2:c.578G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_145814.2(CACNG6):​c.578G>T​(p.Arg193Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNG6 NM_145814.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36

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]

ACMG classification

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, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNG6	NM_145814.2	c.578G>T	p.Arg193Leu	missense_variant	Exon 4 of 4	ENST00000252729.7	NP_665813.1
CACNG6	NM_145815.2	c.440G>T	p.Arg147Leu	missense_variant	Exon 3 of 3		NP_665814.1
CACNG6	NM_031897.3	c.365G>T	p.Arg122Leu	missense_variant	Exon 2 of 2		NP_114103.2
CACNG6	NR_102308.2	n.158G>T		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNG6	ENST00000252729.7	c.578G>T	p.Arg193Leu	missense_variant	Exon 4 of 4	1	NM_145814.2	ENSP00000252729.2
CACNG6	ENST00000346968.2	c.440G>T	p.Arg147Leu	missense_variant	Exon 3 of 3	5		ENSP00000319097.2
CACNG6	ENST00000352529.1	c.365G>T	p.Arg122Leu	missense_variant	Exon 2 of 2	5		ENSP00000319135.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1433268 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 713170

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.578G>T (p.R193L) alteration is located in exon 4 (coding exon 4) of the CACNG6 gene. This alteration results from a G to T substitution at nucleotide position 578, causing the arginine (R) at amino acid position 193 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	0.43
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.6	.;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.69
MutPred		0.70		.;Loss of MoRF binding (P = 0.0815);.;
MVP		0.89
MPC		1.6
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.47
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

Other links and lift over

dbSNP: rs139947484; hg19: chr19-54515238;