rs768950814

Variant names:

• chr19-13208877-G-GGGT
• rs768950814
• NM_001127222.2:c.6658_6659insACC

Your query was ambiguous. Multiple possible variants found:

• chr19-13208877-G-GGGT
• chr19-13208877-G-GGGTGGT
• chr19-13208877-G-GGGTGGTGGT
• chr19-13208877-G-GGGTGGTGGTGGT
• chr19-13208877-G-GGGTGGTGGTGGTGGTGGT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.6658_6659insACC​(p.His2219dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00772 in 1,459,614 control chromosomes in the GnomAD database, including 51 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P2220P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0080 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0077 (39 hom.)
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 5.98
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 19-13208877-G-GGGT is Benign according to our data. Variant chr19-13208877-G-GGGT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210557.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00801 (1206/150552) while in subpopulation AFR AF = 0.0144 (589/40972). AF 95% confidence interval is 0.0134. There are 12 homozygotes in GnomAd4. There are 563 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6658_6659insACC	p.His2219dup	conservative_inframe_insertion	Exon 46 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6658_6659insACC	p.His2219dup	conservative_inframe_insertion	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6676_6677insACC	p.His2225dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6664_6665insACC	p.His2221dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6625_6626insACC	p.His2208dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6520_6521insACC	p.His2173dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6676_6677insACC	p.His2225dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6667_6668insACC	p.His2222dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6664_6665insACC	p.His2221dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6625_6626insACC	p.His2208dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.*924_*925insACC		non_coding_transcript_exon_variant	Exon 44 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1837_*1838insACC		non_coding_transcript_exon_variant	Exon 46 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2	n.*924_*925insACC		3_prime_UTR_variant	Exon 44 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1837_*1838insACC		3_prime_UTR_variant	Exon 46 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.00797 AC: 1199 AN: 150444 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00664

Gnomad AMR AF: 0.00482

Gnomad ASJ AF: 0.00665

Gnomad EAS AF: 0.00697

Gnomad SAS AF: 0.00886

Gnomad FIN AF: 0.000863

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00585

Gnomad OTH AF: 0.0111

GnomAD2 exomes AF: 0.00868 AC: 1019 AN: 117448 AF XY: 0.00894

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.00947

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00596

Gnomad OTH exome AF: 0.00851

GnomAD4 exome AF: 0.00768 AC: 10058 AN: 1309062 Hom.: 39 Cov.: 74 AF XY: 0.00774 AC XY: 5008 AN XY: 646624

African (AFR) AF: 0.0184 AC: 532 AN: 28984

American (AMR) AF: 0.00696 AC: 236 AN: 33890

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 250 AN: 24010

East Asian (EAS) AF: 0.00652 AC: 215 AN: 32960

South Asian (SAS) AF: 0.0119 AC: 906 AN: 76330

European-Finnish (FIN) AF: 0.00140 AC: 45 AN: 32216

Middle Eastern (MID) AF: 0.00932 AC: 49 AN: 5256

European-Non Finnish (NFE) AF: 0.00713 AC: 7281 AN: 1020678

Other (OTH) AF: 0.00994 AC: 544 AN: 54738

GnomAD4 genome AF: 0.00801 AC: 1206 AN: 150552 Hom.: 12 Cov.: 31 AF XY: 0.00766 AC XY: 563 AN XY: 73524

African (AFR) AF: 0.0144 AC: 589 AN: 40972

American (AMR) AF: 0.00482 AC: 73 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.00665 AC: 23 AN: 3460

East Asian (EAS) AF: 0.00719 AC: 36 AN: 5006

South Asian (SAS) AF: 0.00929 AC: 44 AN: 4734

European-Finnish (FIN) AF: 0.000863 AC: 9 AN: 10434

Middle Eastern (MID) AF: 0.0276 AC: 8 AN: 290

European-Non Finnish (NFE) AF: 0.00585 AC: 395 AN: 67510

Other (OTH) AF: 0.0110 AC: 23 AN: 2090

Alfa AF: 0.00306 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

Jan 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 13, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: PM4:Supporting, BS1, BS2 -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jul 07, 2016

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

Jul 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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		6.0
Mutation Taster		=74/26	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs768950814; hg19: chr19-13319691;