19-13298647-GGCCCTCGCCCTC-GGCCCTCGCCCTCGCCCTC

Variant names:

• chr19-13298647-G-GGCCCTC
• rs764399373
• NM_001127222.2:c.2980_2985dupGAGGGC

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.2980_2985dupGAGGGC​(p.Gly995_Pro996insGluGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,517,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G995G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -1.91
• 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 -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2.
• BP6: Variant 19-13298647-G-GGCCCTC is Benign according to our data. Variant chr19-13298647-G-GGCCCTC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421524.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000592 (90/152032) while in subpopulation AFR AF = 0.00181 (75/41518). AF 95% confidence interval is 0.00148. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 90 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2980_2985dupGAGGGC	p.Gly995_Pro996insGluGly	conservative_inframe_insertion	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_2985dupGAGGGC	p.Gly995_Pro996insGluGly	conservative_inframe_insertion	Exon 19 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2992_2997dupGAGGGC	p.Gly999_Pro1000insGluGly	conservative_inframe_insertion	Exon 19 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2986_2991dupGAGGGC	p.Gly997_Pro998insGluGly	conservative_inframe_insertion	Exon 19 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	Exon 19 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	Exon 19 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	Exon 19 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2842_2847dupGAGGGC	p.Gly949_Pro950insGluGly	conservative_inframe_insertion	Exon 18 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	Exon 19 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2992_2997dupGAGGGC	p.Gly999_Pro1000insGluGly	conservative_inframe_insertion	Exon 19 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	Exon 19 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2986_2991dupGAGGGC	p.Gly997_Pro998insGluGly	conservative_inframe_insertion	Exon 19 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	Exon 19 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	Exon 19 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	Exon 19 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.2983_2988dupGAGGGC		non_coding_transcript_exon_variant	Exon 19 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.2980_2985dupGAGGGC		non_coding_transcript_exon_variant	Exon 19 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 151922 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000105 AC: 12 AN: 114332 AF XY: 0.0000962

Gnomad AFR exome AF: 0.000375

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.000278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000624

Gnomad NFE exome AF: 0.0000728

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000177 AC: 241 AN: 1365414 Hom.: 0 Cov.: 32 AF XY: 0.000169 AC XY: 114 AN XY: 673334

African (AFR) AF: 0.00127 AC: 35 AN: 27618

American (AMR) AF: 0.000190 AC: 6 AN: 31568

Ashkenazi Jewish (ASJ) AF: 0.000167 AC: 4 AN: 23978

East Asian (EAS) AF: 0.0000323 AC: 1 AN: 30926

South Asian (SAS) AF: 0.000105 AC: 8 AN: 76418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48238

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5586

European-Non Finnish (NFE) AF: 0.000166 AC: 177 AN: 1064816

Other (OTH) AF: 0.000142 AC: 8 AN: 56266

GnomAD4 genome AF: 0.000592 AC: 90 AN: 152032 Hom.: 0 Cov.: 33 AF XY: 0.000525 AC XY: 39 AN XY: 74306

African (AFR) AF: 0.00181 AC: 75 AN: 41518

American (AMR) AF: 0.000196 AC: 3 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67950

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

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Oct 23, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: BS1, BS2 -

May 21, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 42 Uncertain:1

May 08, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Apr 03, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

Jun 14, 2021

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		-1.9
Mutation Taster		=78/22	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;