19-13286644-TG-TGG

Variant names:

• chr19-13286644-T-TG
• rs746790849
• NM_001127222.2:c.3411dupC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.3411dupC​(p.Lys1138GlnfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000486 in 1,234,576 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P1137P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.997
• Publications: 4 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-13286644-T-TG is Pathogenic according to our data. Variant chr19-13286644-T-TG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 808473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3411dupC	p.Lys1138GlnfsTer6	frameshift_variant	Exon 20 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2	c.3414dupC	p.Lys1139GlnfsTer6	frameshift_variant	Exon 20 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3411dupC	p.Lys1138GlnfsTer6	frameshift_variant	Exon 20 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2	c.3414dupC	p.Lys1139GlnfsTer6	frameshift_variant	Exon 20 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1	c.3423dupC	p.Lys1142GlnfsTer6	frameshift_variant	Exon 20 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3417dupC	p.Lys1140GlnfsTer6	frameshift_variant	Exon 20 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3414dupC	p.Lys1139GlnfsTer6	frameshift_variant	Exon 20 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3414dupC	p.Lys1139GlnfsTer6	frameshift_variant	Exon 20 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3414dupC	p.Lys1139GlnfsTer6	frameshift_variant	Exon 20 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3273dupC	p.Lys1092GlnfsTer6	frameshift_variant	Exon 19 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3414dupC	p.Lys1139GlnfsTer6	frameshift_variant	Exon 20 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3423dupC	p.Lys1142GlnfsTer6	frameshift_variant	Exon 20 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3414dupC	p.Lys1139GlnfsTer6	frameshift_variant	Exon 20 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3417dupC	p.Lys1140GlnfsTer6	frameshift_variant	Exon 20 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3414dupC	p.Lys1139GlnfsTer6	frameshift_variant	Exon 20 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.3414dupC	p.Lys1139GlnfsTer6	frameshift_variant	Exon 20 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.3414dupC		non_coding_transcript_exon_variant	Exon 20 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.3411dupC		non_coding_transcript_exon_variant	Exon 20 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000644 AC: 12 AN: 186272 AF XY: 0.0000101

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000486 AC: 6 AN: 1234576 Hom.: 0 Cov.: 35 AF XY: 0.00000496 AC XY: 3 AN XY: 605246

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

African (AFR) AF: 0.00 AC: 0 AN: 26942

American (AMR) AF: 0.00 AC: 0 AN: 29612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15894

East Asian (EAS) AF: 0.00 AC: 0 AN: 25886

South Asian (SAS) AF: 0.00 AC: 0 AN: 73182

European-Finnish (FIN) AF: 0.0000899 AC: 3 AN: 33368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4596

European-Non Finnish (NFE) AF: 0.00000307 AC: 3 AN: 977654

Other (OTH) AF: 0.00 AC: 0 AN: 47442

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000113363), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 2 Pathogenic:1

Jul 06, 2021

Research Unit of Clinical Medicine, Medical Research Center Oulu, University of Oulu

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant was found in a patient with dominantly inherited ataxia. The mutation causes a frameshift and early termination of the protein suggesting pathogenicity. However, functional studies and segregation analyses are required to confirm the pathogenicity of the variant.

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1

Feb 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys1139Glnfs*6) in the CACNA1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with episodic ataxia (PMID: 12736095). This variant is also known as Insertion C after 3689. ClinVar contains an entry for this variant (Variation ID: 808473). For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=0/200	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: rs746790849; hg19: chr19-13397458; COSMIC: COSV64190022; COSMIC: COSV64190022;