rs781315664

Variant names:

• chr12-2664961-A-C
• rs781315664
• NM_000719.7:c.4369A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-2664961-A-C
• chr12-2664961-A-G
• chr12-2664961-A-T

Variant summary

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

The NM_000719.7(CACNA1C):​c.4369A>C​(p.Ile1457Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I1457F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4603A>C	p.Ile1535Leu	missense_variant	Exon 37 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4336A>C	p.Ile1446Leu	missense_variant	Exon 34 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4534A>C	p.Ile1512Leu	missense_variant	Exon 36 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4513A>C	p.Ile1505Leu	missense_variant	Exon 37 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4435A>C	p.Ile1479Leu	missense_variant	Exon 35 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4459A>C	p.Ile1487Leu	missense_variant	Exon 35 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4459A>C	p.Ile1487Leu	missense_variant	Exon 35 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4459A>C	p.Ile1487Leu	missense_variant	Exon 35 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4459A>C	p.Ile1487Leu	missense_variant	Exon 35 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4453A>C	p.Ile1485Leu	missense_variant	Exon 36 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4444A>C	p.Ile1482Leu	missense_variant	Exon 36 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4429A>C	p.Ile1477Leu	missense_variant	Exon 36 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4420A>C	p.Ile1474Leu	missense_variant	Exon 35 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4411A>C	p.Ile1471Leu	missense_variant	Exon 35 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4336A>C	p.Ile1446Leu	missense_variant	Exon 34 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4336A>C	p.Ile1446Leu	missense_variant	Exon 34 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4330A>C	p.Ile1444Leu	missense_variant	Exon 34 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4369A>C	p.Ile1457Leu	missense_variant	Exon 35 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4360A>C	p.Ile1454Leu	missense_variant	Exon 35 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4336A>C	p.Ile1446Leu	missense_variant	Exon 34 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

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: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
CardioboostArm	Benign	0.00041
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.042
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.70	.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		4.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.58
Sift	Benign	0.071	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.45, 0.42, 0.42, 0.29, 0.26, 0.16, 0.13, 0.097, 0.88, 0.11	.;B;B;B;B;B;B;B;B;B;B;B;B;P;B;.;B;B;.;.;.;B;.
Vest4		0.40
MutPred		0.52		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at A1500 (P = 2e-04);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.74
MPC		1.1
ClinPred		0.73	D
GERP RS		4.4
gMVP		0.89
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs781315664; hg19: chr12-2774127;