NM_001127222.2:c.876A>C

Variant names:

• chr19-13359708-T-G
• rs16006
• NM_001127222.2:c.876A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP4

The NM_001127222.2(CACNA1A):​c.876A>C​(p.Glu292Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000838 in 1,419,618 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E292E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0640
• Publications: 10 publications found

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent 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, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

CACNA1A Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001127222.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.33546892).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127222.2. 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
	CACNA1A	NM_001127222.2	MANE Select	c.876A>C	p.Glu292Asp	missense	Exon 6 of 47	NP_001120694.1
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.876A>C	p.Glu292Asp	missense	Exon 6 of 47	NP_001120693.1
	CACNA1A	NM_023035.3		c.876A>C	p.Glu292Asp	missense	Exon 6 of 48	NP_075461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.876A>C	p.Glu292Asp	missense	Exon 6 of 47	ENSP00000353362.5
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.876A>C	p.Glu292Asp	missense	Exon 6 of 47	ENSP00000489913.1
	CACNA1A	ENST00000638029.1	TSL:5	c.876A>C	p.Glu292Asp	missense	Exon 6 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000838 AC: 119 AN: 1419618 Hom.: 0 Cov.: 31 AF XY: 0.0000837 AC XY: 59 AN XY: 705054

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000609 AC: 2 AN: 32834

American (AMR) AF: 0.00 AC: 0 AN: 41362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25578

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38710

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82500

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.000102 AC: 110 AN: 1081746

Other (OTH) AF: 0.0000339 AC: 2 AN: 59048

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.0060
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.0	L
PhyloP100		0.064
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.49
Sift	Benign	0.59	T
Sift4G	Benign	0.62	T
Polyphen		0.96	D
Vest4		0.19
MutPred		0.46		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.93
MPC		2.0
ClinPred		0.53	D
GERP RS		2.2
Varity_R		0.088
gMVP		0.86
Mutation Taster		=76/24	polymorphism

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: rs16006; hg19: chr19-13470522;