rs749298267

Variant names:

• chr12-2648496-T-C
• rs749298267
• NM_000719.7:c.3934T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000719.7(CACNA1C):​c.3934T>C​(p.Ser1312Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,636 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: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01
• Publications: 2 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20530754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4168T>C	p.Ser1390Pro	missense_variant	Exon 33 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000683824.1	c.4099T>C	p.Ser1367Pro	missense_variant	Exon 32 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4078T>C	p.Ser1360Pro	missense_variant	Exon 33 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4024T>C	p.Ser1342Pro	missense_variant	Exon 31 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4024T>C	p.Ser1342Pro	missense_variant	Exon 31 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4024T>C	p.Ser1342Pro	missense_variant	Exon 31 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4024T>C	p.Ser1342Pro	missense_variant	Exon 31 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4018T>C	p.Ser1340Pro	missense_variant	Exon 32 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4009T>C	p.Ser1337Pro	missense_variant	Exon 32 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3994T>C	p.Ser1332Pro	missense_variant	Exon 32 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399597.5	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3934T>C	p.Ser1312Pro	missense_variant	Exon 31 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3925T>C	p.Ser1309Pro	missense_variant	Exon 31 of 47			ENSP00000507169.1
CACNA1C	ENST00000399634.6	c.3913-3144T>C		intron_variant	Intron 30 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000399629.5	c.3997-3144T>C		intron_variant	Intron 31 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3988-3144T>C		intron_variant	Intron 31 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3913-3144T>C		intron_variant	Intron 30 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3913-3144T>C		intron_variant	Intron 30 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3907-3144T>C		intron_variant	Intron 30 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000682686.1	c.3913-3144T>C		intron_variant	Intron 30 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249274 AF XY: 0.00000739

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111816

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Feb 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with proline at codon 1312 of the CACNA1C protein (p.Ser1312Pro). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs749298267, ExAC 0.001%) but has not been reported in the literature in individuals with a CACNA1C-related disease. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Benign	0.0000041
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.56	.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.
PhyloP100		4.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.24	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0040, 0.0020, 0.0010, 0.021	.;B;B;B;B;B;B;B;B;B;B;B;.;B;.;.;.;B
Vest4		0.46
MutPred		0.51		.;.;.;.;.;.;.;.;Gain of catalytic residue at S1360 (P = 0);.;.;.;.;.;.;.;.;.;
MVP		0.42
MPC		1.6
ClinPred		0.40	T
GERP RS		5.6
gMVP		0.95
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs749298267; hg19: chr12-2757662;