Genetic Variant NM_001127222.2:c.6967_6975delCAGCAGCAG (chr19-13207858-CCTGCTGCTG-C) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3BP6_ModerateBS1BS2

The NM_001127222.2(CACNA1A):c.6967_6975delCAGCAGCAG(p.Gln2323_Gln2325del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,370,548 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 0)

Exomes 𝑓: 0.0027 ( 4 hom. )

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.785

Publications

10 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
developmental and epileptic encephalopathy, 42
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
migraine, familial hemiplegic, 1
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
spinocerebellar ataxia type 6
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
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

CACNA1A links:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001127222.2

BP6

Variant 19-13207858-CCTGCTGCTG-C is Benign according to our data. Variant chr19-13207858-CCTGCTGCTG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2578818.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00325 (481/147858) while in subpopulation AFR AF = 0.00963 (387/40188). AF 95% confidence interval is 0.00884. There are 3 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 481 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127222.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1A	NM_001127222.2	MANE Select	c.6967_6975delCAGCAGCAG	p.Gln2323_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	NP_001120694.1	O00555-8
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.179_187delCAGCAGCAG		3_prime_UTR	Exon 47 of 47	NP_001120693.1	O00555-3
CACNA1A	NM_023035.3		c.6985_6993delCAGCAGCAG	p.Gln2329_Gln2331del	conservative_inframe_deletion	Exon 48 of 48	NP_075461.2	A0A087WW63

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.6967_6975delCAGCAGCAG	p.Gln2323_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1	TSL:5	c.6985_6993delCAGCAGCAG	p.Gln2329_Gln2331del	conservative_inframe_deletion	Exon 48 of 48	ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7	TSL:5	c.6973_6981delCAGCAGCAG	p.Gln2325_Gln2327del	conservative_inframe_deletion	Exon 47 of 47	ENSP00000460092.3	A0A1C7CYY9

Frequencies

GnomAD3 genomes

AF:

0.00324

AC:

478

AN:

147756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00961

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00134

Gnomad ASJ

AF:

0.00378

Gnomad EAS

AF:

0.00207

Gnomad SAS

AF:

0.00149

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000586

Gnomad OTH

AF:

0.00198

GnomAD2 exomes

AF:

0.00563

AC:

293

AN:

52038

AF XY:

0.00609

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.00657

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.00211

Gnomad NFE exome

AF:

0.00431

Gnomad OTH exome

AF:

0.00329

GnomAD4 exome

AF:

0.00269

AC:

3293

AN:

1222690

Hom.:

AF XY:

0.00289

AC XY:

1735

AN XY:

601300

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0146

AC:

318

AN:

21734

American (AMR)

AF:

0.00838

AC:

192

AN:

22900

Ashkenazi Jewish (ASJ)

AF:

0.00729

AC:

147

AN:

20156

East Asian (EAS)

AF:

0.00184

AC:

AN:

28808

South Asian (SAS)

AF:

0.00810

AC:

501

AN:

61830

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

32428

Middle Eastern (MID)

AF:

0.00596

AC:

AN:

3358

European-Non Finnish (NFE)

AF:

0.00185

AC:

1811

AN:

981190

Other (OTH)

AF:

0.00378

AC:

190

AN:

50286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.306

Heterozygous variant carriers

364

728

1093

1457

1821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00325

AC:

481

AN:

147858

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

226

AN XY:

71970

show subpopulations

African (AFR)

AF:

0.00963

AC:

387

AN:

40188

American (AMR)

AF:

0.00134

AC:

AN:

14960

Ashkenazi Jewish (ASJ)

AF:

0.00378

AC:

AN:

3436

East Asian (EAS)

AF:

0.00208

AC:

AN:

4814

South Asian (SAS)

AF:

0.00149

AC:

AN:

4704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9944

Middle Eastern (MID)

AF:

0.00362

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000586

AC:

AN:

66596

Other (OTH)

AF:

0.00196

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

195

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

CACNA1A-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.79

Mutation Taster

=197/3

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over