rs1555558553

Variant names:

• chr17-50607905-A-G
• rs1555558553
• NM_018896.5:c.4591A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_018896.5(CACNA1G):​c.4591A>G​(p.Met1531Val) variant causes a missense change involving the alteration of a 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 Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV002768702: "Moderate functional evidence supporting abnormal protein function. Functional studies demonstrated altered electrophysiological behaviour and increased calcium influx (PMID:29878067)"". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1531L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1G NM_018896.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32
• Publications: 7 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• spinocerebellar ataxia type 42

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), 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: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002768702: "Moderate functional evidence supporting abnormal protein function. Functional studies demonstrated altered electrophysiological behaviour and increased calcium influx (PMID: 29878067)"
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_018896.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-50607905-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3256767.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant 17-50607905-A-G is Pathogenic according to our data. Variant chr17-50607905-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 559581.Status of the report is criteria_provided_single_submitter, 1 stars.

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.4591A>G	p.Met1531Val	missense	Exon 25 of 38	NP_061496.2
	CACNA1G	NM_198377.3		c.4591A>G	p.Met1531Val	missense	Exon 25 of 37	NP_938191.2	O43497-20
	CACNA1G	NM_198396.3		c.4522A>G	p.Met1508Val	missense	Exon 24 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.4591A>G	p.Met1531Val	missense	Exon 25 of 38	ENSP00000352011.5	O43497-1
	CACNA1G	ENST00000507336.5	TSL:1	c.4591A>G	p.Met1531Val	missense	Exon 25 of 37	ENSP00000420918.1	O43497-20
	CACNA1G	ENST00000507510.6	TSL:1	c.4591A>G	p.Met1531Val	missense	Exon 25 of 37	ENSP00000423112.2	O43497-12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.66	P
Vest4		0.62
MutPred		0.76		Loss of helix (P = 0.0237)
MVP		0.99
MPC		1.9
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.78
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1555558553; hg19: chr17-48685266;