NM_001127222.2:c.5891_5892delACinsGT

Variant names:

• chr19-13214281-GT-AC
• NM_001127222.2:c.5891_5892delACinsGT
• CACNA1A p.Tyr1964Cys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001127222.2(CACNA1A):c.5891_5892delACinsGT (p.Tyr1964Cys) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.Y1964C: Uncertain_significance (ClinVar VariationId 522072, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.68
• Publications: 0 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• undetermined early-onset epileptic encephalopathy

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

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

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

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

ENSG00000300728 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 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/XL) (base 0.0001, raised to 0.000117 by highest known P/LP ClinVar AF 0.000117) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001127222.2. 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
	CACNA1A NM_001127222.2	MANE Select	c.5891_5892delACinsGT p.Tyr1964Cys	missense	N/A	Prot: NP_001120694.1 UniProt:
	CACNA1A NM_001127221.2	MANE Plus Clinical	c.5894_5895delACinsGT p.Tyr1965Cys	missense	N/A	Prot: NP_001120693.1 UniProt:
	CACNA1A NM_023035.3		c.5909_5910delACinsGT p.Tyr1970Cys	missense	N/A	Prot: NP_075461.2 UniProt:

CACNA1A NM_001127222.2

MANE Select

HGVSc / HGVSpc.5891_5892delACinsGTp.Tyr1964Cys

Exon rankN/A

missense

Prot: NP_001120694.1UniProt: O00555-8

CACNA1A NM_001127221.2

MANE Plus Clinical

HGVSc / HGVSpc.5894_5895delACinsGTp.Tyr1965Cys

Exon rankN/A

missense

Prot: NP_001120693.1UniProt: O00555-3

CACNA1A NM_023035.3

HGVSc / HGVSpc.5909_5910delACinsGTp.Tyr1970Cys

Exon rankN/A

missense

Prot: NP_075461.2UniProt: A0A087WW63

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CACNA1A ENST00000360228.11	TSL:1MANE Select	c.5891_5892delACinsGT p.Tyr1964Cys	missense	N/A	Prot: ENSP00000353362.5 UniProt:
	CACNA1A ENST00000638009.2	TSL:1MANE Plus Clinical	c.5894_5895delACinsGT p.Tyr1965Cys	missense	N/A	Prot: ENSP00000489913.1 UniProt:
	CACNA1A ENST00000638029.1	TSL:5	c.5909_5910delACinsGT p.Tyr1970Cys	missense	N/A	Prot: ENSP00000489829.1 UniProt:

CACNA1A ENST00000360228.11

TSL:1MANE Select

HGVSc / HGVSpc.5891_5892delACinsGTp.Tyr1964Cys

Exon rankN/A

missense

Prot: ENSP00000353362.5UniProt: O00555-8

CACNA1A ENST00000638009.2

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.5894_5895delACinsGTp.Tyr1965Cys

Exon rankN/A

missense

Prot: ENSP00000489913.1UniProt: O00555-3

CACNA1A ENST00000638029.1

TSL:5

HGVSc / HGVSpc.5909_5910delACinsGTp.Tyr1970Cys

Exon rankN/A

missense

Prot: ENSP00000489829.1UniProt: A0A087WW63

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	2.7

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr19-13325095;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar