chr17-50616335-T-C

Variant names:

• chr17-50616335-T-C
• rs1555565684
• NM_018896.5:c.4972T>C

Variant summary

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

The NM_018896.5(CACNA1G):​c.4972T>C​(p.Ser1658Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1G NM_018896.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28
• Publications: 0 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: 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, 0.932

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1G	NM_018896.5	MANE Select	c.4972T>C	p.Ser1658Pro	missense	Exon 28 of 38	NP_061496.2
	CACNA1G	NM_198377.3		c.4939T>C	p.Ser1647Pro	missense	Exon 27 of 37	NP_938191.2
	CACNA1G	NM_198396.3		c.4870T>C	p.Ser1624Pro	missense	Exon 26 of 36	NP_938406.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1G	ENST00000359106.10	TSL:1 MANE Select	c.4972T>C	p.Ser1658Pro	missense	Exon 28 of 38	ENSP00000352011.5
	CACNA1G	ENST00000507336.5	TSL:1	c.4939T>C	p.Ser1647Pro	missense	Exon 27 of 37	ENSP00000420918.1
	CACNA1G	ENST00000507510.6	TSL:1	c.4972T>C	p.Ser1658Pro	missense	Exon 28 of 37	ENSP00000423112.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 42 Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.77		Loss of MoRF binding (P = 0.0896)
MVP		0.94
MPC		2.5
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.96
gMVP		1.0

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: rs1555565684; hg19: chr17-48693696;