rs771768635

Variant names:

• chr19-13212496-T-C
• rs771768635
• NM_001127222.2:c.6077A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001127222.2(CACNA1A):​c.6077A>G​(p.Glu2026Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000907 in 1,433,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.78
• 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

ENSG00000300728 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1623317).
• BP6: Variant 19-13212496-T-C is Benign according to our data. Variant chr19-13212496-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 585579.
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6077A>G	p.Glu2026Gly	missense_variant	Exon 42 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2	c.6080A>G	p.Glu2027Gly	missense_variant	Exon 42 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6077A>G	p.Glu2026Gly	missense_variant	Exon 42 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2	c.6080A>G	p.Glu2027Gly	missense_variant	Exon 42 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1	c.6095A>G	p.Glu2032Gly	missense_variant	Exon 43 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6083A>G	p.Glu2028Gly	missense_variant	Exon 42 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6080A>G	p.Glu2027Gly	missense_variant	Exon 42 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6080A>G	p.Glu2027Gly	missense_variant	Exon 42 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6080A>G	p.Glu2027Gly	missense_variant	Exon 42 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5939A>G	p.Glu1980Gly	missense_variant	Exon 41 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6080A>G	p.Glu2027Gly	missense_variant	Exon 42 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6095A>G	p.Glu2032Gly	missense_variant	Exon 43 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6086A>G	p.Glu2029Gly	missense_variant	Exon 43 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6083A>G	p.Glu2028Gly	missense_variant	Exon 42 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6080A>G	p.Glu2027Gly	missense_variant	Exon 42 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.6080A>G	p.Glu2027Gly	missense_variant	Exon 42 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.*379A>G		non_coding_transcript_exon_variant	Exon 41 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1292A>G		non_coding_transcript_exon_variant	Exon 43 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2	n.*379A>G		3_prime_UTR_variant	Exon 41 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1292A>G		3_prime_UTR_variant	Exon 43 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000557 AC: 11 AN: 197326 AF XY: 0.0000471

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000394

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000907 AC: 13 AN: 1433070 Hom.: 0 Cov.: 34 AF XY: 0.00000563 AC XY: 4 AN XY: 710110

African (AFR) AF: 0.00 AC: 0 AN: 32950

American (AMR) AF: 0.000331 AC: 13 AN: 39222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25450

East Asian (EAS) AF: 0.00 AC: 0 AN: 38344

South Asian (SAS) AF: 0.00 AC: 0 AN: 82700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097732

Other (OTH) AF: 0.00 AC: 0 AN: 59416

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000801 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000665 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Aug 08, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jul 15, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 42 Uncertain:1

Aug 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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;T;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.6	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.
PhyloP100		3.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.8	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.29
Sift	Benign	0.23	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.29	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.36
MutPred		0.33		.;.;Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);.;.;Loss of solvent accessibility (P = 0.0187);.;.;.;Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);.;Loss of solvent accessibility (P = 0.0187);.;.;.;
MVP		0.85
MPC		0.70
ClinPred		0.64	D
GERP RS		3.1
Varity_R		0.24
gMVP		0.57
Mutation Taster		=65/35	polymorphism

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: rs771768635; hg19: chr19-13323310;