rs1159450845

Variant names:

• chr19-53998254-A-G
• rs1159450845
• NM_145814.2:c.347A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_145814.2(CACNG6):​c.347A>G​(p.Tyr116Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CACNG6 NM_145814.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145814.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNG6	NM_145814.2	MANE Select	c.347A>G	p.Tyr116Cys	missense	Exon 2 of 4	NP_665813.1	Q9BXT2
	CACNG6	NM_145815.2		c.347A>G	p.Tyr116Cys	missense	Exon 2 of 3	NP_665814.1	A6NFR2
	CACNG6	NM_031897.3		c.331+5046A>G		intron	N/A	NP_114103.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNG6	ENST00000252729.7	TSL:1 MANE Select	c.347A>G	p.Tyr116Cys	missense	Exon 2 of 4	ENSP00000252729.2	Q9BXT2
	CACNG6	ENST00000346968.2	TSL:5	c.347A>G	p.Tyr116Cys	missense	Exon 2 of 3	ENSP00000319097.2	A6NFR2
	CACNG6	ENST00000955412.1		c.332-1380A>G		intron	N/A	ENSP00000625471.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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: 0.00000479 AC: 7 AN: 1461764 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111934

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.84
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.79
gMVP		0.87
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1159450845; hg19: chr19-54501508;