ENST00000406454.8:c.5477C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000406454.8(CACNA1C):c.5477C>T(p.Thr1826Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,406,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/17 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. T1826N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CACNA1C
ENST00000406454.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0620

Publications

2 publications found

Variant links:

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

CACNA1C links:

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

ITFG2-AS1 links:

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05910638).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5444+599C>T		intron_variant	Intron 42 of 46	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.5444+599C>T		intron_variant	Intron 42 of 46	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000406454.8 link	c.5477C>T	p.Thr1826Ile	missense_variant	Exon 43 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.5444C>T	p.Thr1815Ile	missense_variant	Exon 42 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000399603.6 link	c.5444+599C>T		intron_variant	Intron 42 of 46	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.5444+599C>T		intron_variant	Intron 42 of 46	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.5678+599C>T		intron_variant	Intron 44 of 49			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000683824.1 link	c.5609+599C>T		intron_variant	Intron 43 of 47			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.5588+599C>T		intron_variant	Intron 44 of 48	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.5567+599C>T		intron_variant	Intron 42 of 46	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.5444+599C>T		intron_variant	Intron 42 of 47	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.5444+599C>T		intron_variant	Intron 42 of 47	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.5534+599C>T		intron_variant	Intron 42 of 46			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.5534+599C>T		intron_variant	Intron 42 of 46			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.5534+599C>T		intron_variant	Intron 42 of 46			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.5534+599C>T		intron_variant	Intron 42 of 46			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.5528+599C>T		intron_variant	Intron 43 of 47	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.5519+599C>T		intron_variant	Intron 43 of 47	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.5504+599C>T		intron_variant	Intron 43 of 47	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.5501+599C>T		intron_variant	Intron 42 of 46	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.5501+599C>T		intron_variant	Intron 42 of 46	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.5501+599C>T		intron_variant	Intron 42 of 46	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.5495+599C>T		intron_variant	Intron 42 of 46	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.5486+599C>T		intron_variant	Intron 42 of 46			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.5468+599C>T		intron_variant	Intron 41 of 45	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.5468+599C>T		intron_variant	Intron 41 of 45	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.5462+599C>T		intron_variant	Intron 41 of 45	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.5444+599C>T		intron_variant	Intron 42 of 46	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.5444+599C>T		intron_variant	Intron 42 of 46	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.5444+599C>T		intron_variant	Intron 42 of 46	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.5444+599C>T		intron_variant	Intron 42 of 46	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.5444+599C>T		intron_variant	Intron 42 of 46			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.5435+599C>T		intron_variant	Intron 42 of 46			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.5411+599C>T		intron_variant	Intron 41 of 45			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000284

AC:

AN:

1406956

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694778

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32180

American (AMR)

AF:

0.00

AC:

AN:

37036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25226

East Asian (EAS)

AF:

0.00

AC:

AN:

36680

South Asian (SAS)

AF:

0.00

AC:

AN:

79764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49076

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000369

AC:

AN:

1082934

Other (OTH)

AF:

0.00

AC:

AN:

58362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.0

(source)

DANN

Benign

0.45

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.018

M_CAP

Benign

0.049

MetaRNN

Benign

0.059

T;T

MetaSVM

Benign

-0.36

PhyloP100

-0.062

PROVEAN

Benign

-0.49

N;N

REVEL

Benign

0.18

Sift

Benign

0.64

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.0010

.;B

Vest4

0.087

MutPred

0.29

Loss of glycosylation at T1826 (P = 0.0159);Loss of glycosylation at T1826 (P = 0.0159);

MVP

0.34

ClinPred

0.018

GERP RS

-0.59

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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