rs198538

Variant names:

• chr17-50565332-C-T
• rs198538
• NM_018896.5:c.243-3538C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_018896.5(CACNA1G):​c.243-3538C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 146,294 control chromosomes in the GnomAD database, including 6,808 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6808 hom., cov: 29)
• Consequence: CACNA1G NM_018896.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 11 publications found

Genes affected

CACNA1G (HGNC:1394): (calcium voltage-gated channel subunit alpha1 G) Voltage-sensitive calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division, and cell death. This gene encodes a T-type, low-voltage activated calcium channel. The T-type channels generate currents that are both transient, owing to fast inactivation, and tiny, owing to small conductance. T-type channels are thought to be involved in pacemaker activity, low-threshold calcium spikes, neuronal oscillations and resonance, and rebound burst firing. Many alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Sep 2011]

CACNA1G Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia, Ambry Genetics
• spinocerebellar ataxia type 42

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Illumina
• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1G	NM_018896.5	c.243-3538C>T		intron_variant	Intron 1 of 37	ENST00000359106.10	NP_061496.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1G	ENST00000359106.10	c.243-3538C>T		intron_variant	Intron 1 of 37	1	NM_018896.5	ENSP00000352011.5
CACNA1G	ENST00000507510.6	c.243-3538C>T		intron_variant	Intron 1 of 36	1		ENSP00000423112.2

Frequencies

GnomAD3 genomes AF: 0.281 AC: 41136 AN: 146188 Hom.: 6781 Cov.: 29

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.0820

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.262

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.282 AC: 41204 AN: 146294 Hom.: 6808 Cov.: 29 AF XY: 0.279 AC XY: 19766 AN XY: 70862

African (AFR) AF: 0.470 AC: 18673 AN: 39704

American (AMR) AF: 0.303 AC: 4250 AN: 14022

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1085 AN: 3442

East Asian (EAS) AF: 0.0824 AC: 390 AN: 4732

South Asian (SAS) AF: 0.132 AC: 608 AN: 4590

European-Finnish (FIN) AF: 0.225 AC: 2163 AN: 9606

Middle Eastern (MID) AF: 0.191 AC: 54 AN: 282

European-Non Finnish (NFE) AF: 0.198 AC: 13256 AN: 66954

Other (OTH) AF: 0.271 AC: 556 AN: 2054

Alfa AF: 0.222 Hom.: 12119

Bravo AF: 0.292

Asia WGS AF: 0.183 AC: 640 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.74
PhyloP100		1.1
Mutation Taster		=99/1	polymorphism (auto)

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: rs198538; hg19: chr17-48642693;