rs770368215

Variant names:

• chr19-13208877-GGATGGTGGTGGT-G
• rs770368215
• NM_001127222.2:c.6647_6658delACCACCACCATC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM4 PP3 BP6 BS2

The ENST00000637769.1(CACNA1A):​c.6650_6661delACCACCACCATC​(p.His2217_His2220del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,460,020 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H2217H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: CACNA1A ENST00000637769.1 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 8.26
• Publications: 1 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

ENSG00000300728 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000637769.1.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 19-13208877-GGATGGTGGTGGT-G is Benign according to our data. Variant chr19-13208877-GGATGGTGGTGGT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 421166.
• BS2: High AC in GnomAd4 at 27 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000637769.1. 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.6647_6658delACCACCACCATC	p.His2216_His2219del	disruptive_inframe_deletion	Exon 46 of 47	NP_001120694.1
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.6650_6661delACCACCACCATC	p.His2217_His2220del	disruptive_inframe_deletion	Exon 46 of 47	NP_001120693.1
	CACNA1A	NM_023035.3		c.6665_6676delACCACCACCATC	p.His2222_His2225del	disruptive_inframe_deletion	Exon 47 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.6647_6658delACCACCACCATC	p.His2216_His2219del	disruptive_inframe_deletion	Exon 46 of 47	ENSP00000353362.5
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.6650_6661delACCACCACCATC	p.His2217_His2220del	disruptive_inframe_deletion	Exon 46 of 47	ENSP00000489913.1
	CACNA1A	ENST00000638029.1	TSL:5	c.6665_6676delACCACCACCATC	p.His2222_His2225del	disruptive_inframe_deletion	Exon 47 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes AF: 0.000179 AC: 27 AN: 150462 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000252

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000315 AC: 37 AN: 117448 AF XY: 0.000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000277

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000542

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000267 AC: 349 AN: 1309450 Hom.: 0 AF XY: 0.000260 AC XY: 168 AN XY: 646838

African (AFR) AF: 0.000138 AC: 4 AN: 28996

American (AMR) AF: 0.000177 AC: 6 AN: 33894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24028

East Asian (EAS) AF: 0.000182 AC: 6 AN: 32968

South Asian (SAS) AF: 0.000327 AC: 25 AN: 76342

European-Finnish (FIN) AF: 0.0000621 AC: 2 AN: 32216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5258

European-Non Finnish (NFE) AF: 0.000285 AC: 291 AN: 1020992

Other (OTH) AF: 0.000274 AC: 15 AN: 54756

GnomAD4 genome AF: 0.000179 AC: 27 AN: 150570 Hom.: 0 Cov.: 27 AF XY: 0.000163 AC XY: 12 AN XY: 73540

African (AFR) AF: 0.000171 AC: 7 AN: 40984

American (AMR) AF: 0.000132 AC: 2 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.000200 AC: 1 AN: 5006

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000252 AC: 17 AN: 67510

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000282 Hom.: 0

Bravo AF: 0.000185

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	CACNA1A-related disorder (1)
-	1	-	Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3
Mutation Taster		=112/88	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770368215; hg19: chr19-13319691;