17-50616335-T-C

Variant names:

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

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	Prot: NP_061496.2
	CACNA1G NM_198377.3		c.4939T>C p.Ser1647Pro	missense	Exon 27 of 37	Prot: NP_938191.2 UniProt:
	CACNA1G NM_198396.3		c.4870T>C p.Ser1624Pro	missense	Exon 26 of 36	Prot: NP_938406.1 UniProt:

CACNA1G NM_018896.5

MANE Select

HGVSc / HGVSpc.4972T>Cp.Ser1658Pro

Exon rankExon 28 of 38

missense

Prot: NP_061496.2

CACNA1G NM_198377.3

HGVSc / HGVSpc.4939T>Cp.Ser1647Pro

Exon rankExon 27 of 37

missense

Prot: NP_938191.2UniProt: O43497-20

CACNA1G NM_198396.3

HGVSc / HGVSpc.4870T>Cp.Ser1624Pro

Exon rankExon 26 of 36

missense

Prot: NP_938406.1UniProt: O43497-33

Ensembl Transcripts

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

CACNA1G ENST00000359106.10

TSL:1MANE Select

HGVSc / HGVSpc.4972T>Cp.Ser1658Pro

Exon rankExon 28 of 38

missense

Prot: ENSP00000352011.5UniProt: O43497-1

CACNA1G ENST00000507336.5

TSL:1

HGVSc / HGVSpc.4939T>Cp.Ser1647Pro

Exon rankExon 27 of 37

missense

Prot: ENSP00000420918.1UniProt: O43497-20

CACNA1G ENST00000507510.6

TSL:1

HGVSc / HGVSpc.4972T>Cp.Ser1658Pro

Exon rankExon 28 of 37

missense

Prot: ENSP00000423112.2UniProt: 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 pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	28
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
FuncVEP CTI	Pathogenic	0.97
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
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	Benign	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
Varity_R	N/A	0.96
VESM-3B	Benign	-13

Showing 26 of 26 scores

Splicing Scores

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

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1555565684;

hg19: chr17-48693696;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar