chr19-53993145-C-T

Variant names:

• chr19-53993145-C-T
• rs1363538160
• NM_145814.2:c.268C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145814.2(CACNG6):​c.268C>T​(p.Arg90Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000646 in 1,547,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R90L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: CACNG6 NM_145814.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.532
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37173778).

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.268C>T	p.Arg90Trp	missense	Exon 1 of 4	NP_665813.1	Q9BXT2
	CACNG6	NM_145815.2		c.268C>T	p.Arg90Trp	missense	Exon 1 of 3	NP_665814.1	A6NFR2
	CACNG6	NM_031897.3		c.268C>T	p.Arg90Trp	missense	Exon 1 of 2	NP_114103.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNG6	ENST00000252729.7	TSL:1 MANE Select	c.268C>T	p.Arg90Trp	missense	Exon 1 of 4	ENSP00000252729.2	Q9BXT2
	CACNG6	ENST00000955412.1		c.268C>T	p.Arg90Trp	missense	Exon 1 of 3	ENSP00000625471.1
	CACNG6	ENST00000346968.2	TSL:5	c.268C>T	p.Arg90Trp	missense	Exon 1 of 3	ENSP00000319097.2	A6NFR2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD2 exomes AF: 0.00000715 AC: 1 AN: 139908 AF XY: 0.0000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000645 AC: 9 AN: 1395522 Hom.: 0 Cov.: 31 AF XY: 0.00000871 AC XY: 6 AN XY: 688518

African (AFR) AF: 0.00 AC: 0 AN: 31528

American (AMR) AF: 0.0000561 AC: 2 AN: 35648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25084

East Asian (EAS) AF: 0.00 AC: 0 AN: 35680

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078130

Other (OTH) AF: 0.0000173 AC: 1 AN: 57902

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

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	Benign	0.26
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.074
Eigen_PC	Benign	0.016
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.53
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		0.61	P
Vest4		0.43
MutPred		0.40		Loss of methylation at K85 (P = 0.073)
MVP		0.90
MPC		1.4
ClinPred		0.96	D
GERP RS		1.2
PromoterAI		-0.0088	Neutral
Varity_R		0.34
gMVP		0.72
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1363538160; hg19: chr19-54496399;