17-50569650-T-G

Variant names:

• chr17-50569650-T-G
• rs12946808
• NM_018896.5:c.489-56T>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.489-56T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,259,974 control chromosomes in the GnomAD database, including 169,515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16734 hom., cov: 30)
  • Exomes 𝑓: 0.51 (152781 hom.)
• Consequence: CACNA1G NM_018896.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.249
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 17-50569650-T-G is Benign according to our data. Variant chr17-50569650-T-G is described in ClinVar as [Benign]. Clinvar id is 1192601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1G	NM_018896.5	c.489-56T>G		intron_variant	Intron 3 of 37	ENST00000359106.10	NP_061496.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1G	ENST00000359106.10	c.489-56T>G		intron_variant	Intron 3 of 37	1	NM_018896.5	ENSP00000352011.5
CACNA1G	ENST00000507510.6	c.489-56T>G		intron_variant	Intron 3 of 36	1		ENSP00000423112.2

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67297 AN: 151696 Hom.: 16736 Cov.: 30

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.705

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.463

GnomAD4 exome AF: 0.514 AC: 569253 AN: 1108160 Hom.: 152781 AF XY: 0.521 AC XY: 289380 AN XY: 555712

African (AFR) AF: 0.232 AC: 6049 AN: 26104

American (AMR) AF: 0.545 AC: 19147 AN: 35132

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 9974 AN: 23278

East Asian (EAS) AF: 0.931 AC: 31672 AN: 34018

South Asian (SAS) AF: 0.692 AC: 50800 AN: 73456

European-Finnish (FIN) AF: 0.482 AC: 19844 AN: 41180

Middle Eastern (MID) AF: 0.481 AC: 2461 AN: 5118

European-Non Finnish (NFE) AF: 0.493 AC: 405096 AN: 821616

Other (OTH) AF: 0.502 AC: 24210 AN: 48258

GnomAD4 genome AF: 0.443 AC: 67295 AN: 151814 Hom.: 16734 Cov.: 30 AF XY: 0.452 AC XY: 33506 AN XY: 74180

African (AFR) AF: 0.244 AC: 10098 AN: 41394

American (AMR) AF: 0.495 AC: 7569 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1453 AN: 3466

East Asian (EAS) AF: 0.905 AC: 4643 AN: 5132

South Asian (SAS) AF: 0.704 AC: 3375 AN: 4796

European-Finnish (FIN) AF: 0.484 AC: 5111 AN: 10550

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.495 AC: 33633 AN: 67884

Other (OTH) AF: 0.457 AC: 965 AN: 2112

Alfa AF: 0.457 Hom.: 2226

Bravo AF: 0.434

Asia WGS AF: 0.716 AC: 2487 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Spinocerebellar ataxia type 42 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.89
PhyloP100		0.25
PromoterAI		-0.0042	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs12946808; hg19: chr17-48647011;