CACNA1G p.Ser1658Pro

Variant names:

• chr17-50616335-T-C
• rs1555565684
• NM_018896.5:c.4972T>C
• CACNA1G p.Ser1658Pro

Your query was ambiguous. Multiple possible variants found:

• chr17-50616335-T-C
• chr17-50616335-TCA-CCC
• chr17-50616335-TCA-CCG
• chr17-50616335-TCA-CCT

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACMG Germline Pathogenicity v2019). PM2PP3_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 is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 42

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

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

  Inheritance: AR Classification: LIMITED Submitted by: G2P

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_018896.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	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	O43497-20
	CACNA1G	NM_198396.3		c.4870T>C	p.Ser1624Pro	missense	Exon 26 of 36	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.4972T>C	p.Ser1658Pro	missense	Exon 28 of 38	ENSP00000352011.5	O43497-1
	CACNA1G	ENST00000507336.5	TSL:1	c.4939T>C	p.Ser1647Pro	missense	Exon 27 of 37	ENSP00000420918.1	O43497-20
	CACNA1G	ENST00000507510.6	TSL:1	c.4972T>C	p.Ser1658Pro	missense	Exon 28 of 37	ENSP00000423112.2	O43497-12

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spinocerebellar ataxia type 42 (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	28
AlphaMissense	Pathogenic	-	1.0
BayesDel_addAF	Pathogenic	D	0.33
BayesDel_noAF	Pathogenic	-	0.24
CADD	Pathogenic	-	29
DANN	Uncertain	-	1.0
DEOGEN2	Pathogenic	D	0.91
Eigen	Uncertain	-	0.49
Eigen_PC	Uncertain	-	0.47
FATHMM_MKL	Pathogenic	D	0.98
FuncVEP CTI	Pathogenic	-	0.97
GPN-Star LLR	N/A	-	-10
GPN-Star score	N/A	-	10
LIST_S2	Uncertain	D	0.94
M_CAP	Pathogenic	D	0.38
MetaRNN	Pathogenic	D	0.93
MetaSVM	Pathogenic	D	1.0
MutationAssessor	Uncertain	M	2.1
PhyloP100	Benign	-	3.3
PrimateAI	Uncertain	T	0.68
PROVEAN	Uncertain	D	-3.2
REVEL	Pathogenic	-	0.83
Sift	Uncertain	D	0.0020
Sift4G	Uncertain	D	0.0020
Varity_R	N/A	-	0.96
VESM-3B	Benign	-	-13

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.010
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.010

Showing 2 of 2 scores

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: rs1555565684;

hg19: chr17-48693696;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar