NM_001127222.2:c.6659C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001127222.2(CACNA1A):c.6659C>T(p.Pro2220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,459,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2220H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000061 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.81

Publications

1 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: 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

CACNA1A links:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31727397).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6659C>T	p.Pro2220Leu	missense_variant	Exon 46 of 47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 link	c.6659C>T	p.Pro2220Leu	missense_variant	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.6677C>T	p.Pro2226Leu	missense_variant	Exon 47 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.6665C>T	p.Pro2222Leu	missense_variant	Exon 46 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.6662C>T	p.Pro2221Leu	missense_variant	Exon 46 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.6662C>T	p.Pro2221Leu	missense_variant	Exon 46 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.6626C>T	p.Pro2209Leu	missense_variant	Exon 45 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.6521C>T	p.Pro2174Leu	missense_variant	Exon 45 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.6662C>T	p.Pro2221Leu	missense_variant	Exon 46 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.6677C>T	p.Pro2226Leu	missense_variant	Exon 47 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.6668C>T	p.Pro2223Leu	missense_variant	Exon 47 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.6665C>T	p.Pro2222Leu	missense_variant	Exon 46 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.6662C>T	p.Pro2221Leu	missense_variant	Exon 46 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.6662C>T	p.Pro2221Leu	missense_variant	Exon 46 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.6626C>T	p.Pro2209Leu	missense_variant	Exon 45 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.*925C>T		non_coding_transcript_exon_variant	Exon 44 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.*1838C>T		non_coding_transcript_exon_variant	Exon 46 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2 link	n.*925C>T		3_prime_UTR_variant	Exon 44 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.*1838C>T		3_prime_UTR_variant	Exon 46 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150462

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000611

AC:

AN:

1309460

Hom.:

Cov.:

AF XY:

0.00000773

AC XY:

AN XY:

646842

show subpopulations

African (AFR)

AF:

0.0000345

AC:

AN:

28996

American (AMR)

AF:

0.00

AC:

AN:

33894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24028

East Asian (EAS)

AF:

0.00

AC:

AN:

32968

South Asian (SAS)

AF:

0.00

AC:

AN:

76342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5258

European-Non Finnish (NFE)

AF:

0.00000686

AC:

AN:

1021002

Other (OTH)

AF:

0.00

AC:

AN:

54756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00000665

AC:

AN:

150462

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73422

show subpopulations

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

African (AFR)

AF:

0.0000245

AC:

AN:

40868

American (AMR)

AF:

0.00

AC:

AN:

15138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5018

South Asian (SAS)

AF:

0.00

AC:

AN:

4740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67518

Other (OTH)

AF:

0.00

AC:

AN:

2068

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0096

.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.94

D;D;D;D;D;T;D;D;D;D;.;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.32

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

0.14

.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

1.8

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.1

.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.26

Sift

Benign

0.048

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.17

T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.32

MutPred

0.28

.;.;Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);.;.;Loss of relative solvent accessibility (P = 0.0404);.;.;.;.;Loss of relative solvent accessibility (P = 0.0404);.;.;.;.;.;

MVP

0.83

MPC

0.83

ClinPred

0.61

GERP RS

2.7

Varity_R

0.053

gMVP

0.16

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over