19-13298647-GGCCCTCGCCCTC-GGCCCTC

Variant names:

• chr19-13298647-GGCCCTC-G
• rs764399373
• NM_001127222.2:c.2980_2985delGAGGGC

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_001127222.2(CACNA1A):​c.2980_2985delGAGGGC​(p.Glu994_Gly995del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000546 in 1,517,422 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.39
• 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: 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: Benign. The variant received -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2.
• BP6: Variant 19-13298647-GGCCCTC-G is Benign according to our data. Variant chr19-13298647-GGCCCTC-G is described in ClinVar as [Likely_benign]. Clinvar id is 422039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000316 (48/152032) while in subpopulation EAS AF = 0.000582 (3/5152). AF 95% confidence interval is 0.000381. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2980_2985delGAGGGC	p.Glu994_Gly995del	conservative_inframe_deletion	Exon 19 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2980_2985delGAGGGC	p.Glu994_Gly995del	conservative_inframe_deletion	Exon 19 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2992_2997delGAGGGC	p.Glu998_Gly999del	conservative_inframe_deletion	Exon 19 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2986_2991delGAGGGC	p.Glu996_Gly997del	conservative_inframe_deletion	Exon 19 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2983_2988delGAGGGC	p.Glu995_Gly996del	conservative_inframe_deletion	Exon 19 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2983_2988delGAGGGC	p.Glu995_Gly996del	conservative_inframe_deletion	Exon 19 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2983_2988delGAGGGC	p.Glu995_Gly996del	conservative_inframe_deletion	Exon 19 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2842_2847delGAGGGC	p.Glu948_Gly949del	conservative_inframe_deletion	Exon 18 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2983_2988delGAGGGC	p.Glu995_Gly996del	conservative_inframe_deletion	Exon 19 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2992_2997delGAGGGC	p.Glu998_Gly999del	conservative_inframe_deletion	Exon 19 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2983_2988delGAGGGC	p.Glu995_Gly996del	conservative_inframe_deletion	Exon 19 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2986_2991delGAGGGC	p.Glu996_Gly997del	conservative_inframe_deletion	Exon 19 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2983_2988delGAGGGC	p.Glu995_Gly996del	conservative_inframe_deletion	Exon 19 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2983_2988delGAGGGC	p.Glu995_Gly996del	conservative_inframe_deletion	Exon 19 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2983_2988delGAGGGC	p.Glu995_Gly996del	conservative_inframe_deletion	Exon 19 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.2983_2988delGAGGGC		non_coding_transcript_exon_variant	Exon 19 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.2980_2985delGAGGGC		non_coding_transcript_exon_variant	Exon 19 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 151922 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000950

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000245 AC: 28 AN: 114332 AF XY: 0.000256

Gnomad AFR exome AF: 0.000751

Gnomad AMR exome AF: 0.0000518

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000624

Gnomad NFE exome AF: 0.000340

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000572 AC: 781 AN: 1365390 Hom.: 0 AF XY: 0.000575 AC XY: 387 AN XY: 673324

African (AFR) AF: 0.000109 AC: 3 AN: 27618

American (AMR) AF: 0.0000634 AC: 2 AN: 31564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23978

East Asian (EAS) AF: 0.0000647 AC: 2 AN: 30926

South Asian (SAS) AF: 0.000602 AC: 46 AN: 76416

European-Finnish (FIN) AF: 0.000124 AC: 6 AN: 48236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.000631 AC: 672 AN: 1064802

Other (OTH) AF: 0.000889 AC: 50 AN: 56264

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74306

African (AFR) AF: 0.000145 AC: 6 AN: 41518

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5152

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0000950 AC: 1 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 67950

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000291

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: BP3 -

Oct 27, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 25, 2021

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Sep 16, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CACNA1A-related disorder Benign:1

May 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=155/45	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs764399373; hg19: chr19-13409461; COSMIC: COSV107466761;