Variant 12-2680395-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_001167625.2(CACNA1C):c.5444C>T(p.Thr1815Ile) 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. 13/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CACNA1C
NM_001167625.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0620

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:

CACNA1C-AS1 (HGNC:):

CACNA1C-AS1 links:

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

CACNA1C-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ: 6.4654 (greater than the threshold 3.09). Trascript score misZ: 7.0515 (greater than threshold 3.09). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the gene with intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5444+599C>T		intron_variant		ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.5444+599C>T		intron_variant		ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000369

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.0

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over