19-54011957-T-A

Position:

• chr19-54011957-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145814.2(CACNG6):​c.551T>A​(p.Leu184Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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: 3.46

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNG6	NM_145814.2	c.551T>A	p.Leu184Gln	missense_variant	4/4	ENST00000252729.7
CACNG6	NM_145815.2	c.413T>A	p.Leu138Gln	missense_variant	3/3
CACNG6	NM_031897.3	c.338T>A	p.Leu113Gln	missense_variant	2/2
CACNG6	NR_102308.2	n.131T>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNG6	ENST00000252729.7	c.551T>A	p.Leu184Gln	missense_variant	4/4	1	NM_145814.2	P1
CACNG6	ENST00000346968.2	c.413T>A	p.Leu138Gln	missense_variant	3/3	5
CACNG6	ENST00000352529.1	c.338T>A	p.Leu113Gln	missense_variant	2/2	5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1370178 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 676028

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

The c.551T>A (p.L184Q) alteration is located in exon 4 (coding exon 4) of the CACNG6 gene. This alteration results from a T to A substitution at nucleotide position 551, causing the leucine (L) at amino acid position 184 to be replaced by a glutamine (Q). 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	0.65
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.70	T;D;T
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.5	.;M;.
MutationTaster	Benign	0.99	D;D;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.69
MutPred		0.68		.;Loss of stability (P = 0.0125);.;
MVP		0.80
MPC		1.4
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.47
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2069720233; hg19: chr19-54515211;