rs745856938

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000719.7(CACNA1C):c.953T>C(p.Leu318Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,678 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.66

Publications

0 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 Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000719.7

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24092394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1043T>C	p.Leu348Pro	missense_variant	Exon 7 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1043T>C	p.Leu348Pro	missense_variant	Exon 7 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1043T>C	p.Leu348Pro	missense_variant	Exon 7 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1043T>C	p.Leu348Pro	missense_variant	Exon 7 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1043T>C	p.Leu348Pro	missense_variant	Exon 7 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1043T>C	p.Leu348Pro	missense_variant	Exon 7 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.944T>C	p.Leu315Pro	missense_variant	Exon 7 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.953T>C	p.Leu318Pro	missense_variant	Exon 7 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.890T>C	p.Leu297Pro	missense_variant	Exon 6 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.953T>C		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000804

AC:

AN:

248838

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111846

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Mar 28, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs745856938, ExAC 0.002%) but has not been reported in the literature in individuals with a CACNA1C-related disease. This sequence change replaces leucine with proline at codon 318 of the CACNA1C protein (p.Leu318Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline.

Cardiovascular phenotype

Uncertain:1

Jul 20, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L318P variant (also known as c.953T>C), located in coding exon 7 of the CACNA1C gene, results from a T to C substitution at nucleotide position 953. The leucine at codon 318 is replaced by proline, an amino acid with similar properties. According to data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, the association of this alteration with CACNA1C-related neurodevelopmental disorder is unknown; however, the association with CACNA1C-related arrhythmia is unlikely.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

CardioboostArm

Benign

0.0000077

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.53

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

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.24

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

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

0.0

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

PhyloP100

2.7

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.5

N;N;N;D;N;D;N;N;N;D;N;D;N;N;N;D;N;D;N;N;D;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.25

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

Sift4G

Benign

0.33

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

Vest4

0.21

ClinPred

0.30

GERP RS

5.1

gMVP

0.96

Mutation Taster

=68/32

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over