rs198550

Variant names:

• chr17-50575514-A-G
• rs198550
• NM_018896.5:c.1141-29A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018896.5(CACNA1G):​c.1141-29A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,575,772 control chromosomes in the GnomAD database, including 250,866 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26971 hom., cov: 32)
  • Exomes 𝑓: 0.55 (223895 hom.)
• Consequence: CACNA1G NM_018896.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.81
• Publications: 13 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, Ambry Genetics
• spinocerebellar ataxia type 42

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, Illumina, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-50575514-A-G is Benign according to our data. Variant chr17-50575514-A-G is described in ClinVar as Benign. ClinVar VariationId is 1192603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018896.5. 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
	CACNA1G	NM_018896.5	MANE Select	c.1141-29A>G		intron	N/A	NP_061496.2
	CACNA1G	NM_198377.3		c.1141-29A>G		intron	N/A	NP_938191.2	O43497-20
	CACNA1G	NM_198396.3		c.1141-29A>G		intron	N/A	NP_938406.1	O43497-33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1G	ENST00000359106.10	TSL:1 MANE Select	c.1141-29A>G		intron	N/A	ENSP00000352011.5	O43497-1
	CACNA1G	ENST00000507336.5	TSL:1	c.1141-29A>G		intron	N/A	ENSP00000420918.1	O43497-20
	CACNA1G	ENST00000507510.6	TSL:1	c.1141-29A>G		intron	N/A	ENSP00000423112.2	O43497-12

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89291 AN: 151950 Hom.: 26924 Cov.: 32

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.935

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.569

GnomAD2 exomes AF: 0.600 AC: 133853 AN: 222978 AF XY: 0.598

Gnomad AFR exome AF: 0.645

Gnomad AMR exome AF: 0.620

Gnomad ASJ exome AF: 0.490

Gnomad EAS exome AF: 0.938

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.530

Gnomad OTH exome AF: 0.559

GnomAD4 exome AF: 0.554 AC: 789265 AN: 1423704 Hom.: 223895 Cov.: 35 AF XY: 0.557 AC XY: 391411 AN XY: 702558

African (AFR) AF: 0.640 AC: 20849 AN: 32568

American (AMR) AF: 0.618 AC: 25749 AN: 41642

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 12114 AN: 24706

East Asian (EAS) AF: 0.948 AC: 36960 AN: 38984

South Asian (SAS) AF: 0.673 AC: 55269 AN: 82066

European-Finnish (FIN) AF: 0.564 AC: 29402 AN: 52112

Middle Eastern (MID) AF: 0.511 AC: 2138 AN: 4186

European-Non Finnish (NFE) AF: 0.527 AC: 573869 AN: 1088958

Other (OTH) AF: 0.563 AC: 32915 AN: 58482

GnomAD4 genome AF: 0.588 AC: 89388 AN: 152068 Hom.: 26971 Cov.: 32 AF XY: 0.593 AC XY: 44100 AN XY: 74344

African (AFR) AF: 0.639 AC: 26497 AN: 41466

American (AMR) AF: 0.579 AC: 8845 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1720 AN: 3470

East Asian (EAS) AF: 0.935 AC: 4839 AN: 5178

South Asian (SAS) AF: 0.694 AC: 3354 AN: 4830

European-Finnish (FIN) AF: 0.572 AC: 6044 AN: 10570

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36444 AN: 67958

Other (OTH) AF: 0.574 AC: 1210 AN: 2108

Alfa AF: 0.553 Hom.: 98534

Bravo AF: 0.589

Asia WGS AF: 0.809 AC: 2809 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits (1)
-	-	1	Spinocerebellar ataxia type 42 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.053
DANN	Benign	0.35
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs198550;

hg19: chr17-48652875;