chr12-2679472-T-C

Position:

• chr12-2679472-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BS1_Supporting BS2

The NM_000719.7(CACNA1C):​c.5120T>C​(p.Val1707Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,592,324 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1707I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.44

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• 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 7.2674 (greater than threshold 3.09). GenCC has associacion of 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=0.09926).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000723 (11/152186) while in subpopulation EAS AF= 0.00213 (11/5154). AF 95% confidence interval is 0.0012. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5120T>C	p.Val1707Ala	missense_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5120T>C	p.Val1707Ala	missense_variant	42/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5120T>C	p.Val1707Ala	missense_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5120T>C	p.Val1707Ala	missense_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5354T>C	p.Val1785Ala	missense_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5120T>C	p.Val1707Ala	missense_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5087T>C	p.Val1696Ala	missense_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5285T>C	p.Val1762Ala	missense_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5264T>C	p.Val1755Ala	missense_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5243T>C	p.Val1748Ala	missense_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5120T>C	p.Val1707Ala	missense_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5120T>C	p.Val1707Ala	missense_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5210T>C	p.Val1737Ala	missense_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5210T>C	p.Val1737Ala	missense_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5210T>C	p.Val1737Ala	missense_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5210T>C	p.Val1737Ala	missense_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5204T>C	p.Val1735Ala	missense_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5195T>C	p.Val1732Ala	missense_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5180T>C	p.Val1727Ala	missense_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5177T>C	p.Val1726Ala	missense_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5177T>C	p.Val1726Ala	missense_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5177T>C	p.Val1726Ala	missense_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5171T>C	p.Val1724Ala	missense_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5162T>C	p.Val1721Ala	missense_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5144T>C	p.Val1715Ala	missense_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5144T>C	p.Val1715Ala	missense_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5138T>C	p.Val1713Ala	missense_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5120T>C	p.Val1707Ala	missense_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5120T>C	p.Val1707Ala	missense_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5120T>C	p.Val1707Ala	missense_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5120T>C	p.Val1707Ala	missense_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5120T>C	p.Val1707Ala	missense_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5111T>C	p.Val1704Ala	missense_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5087T>C	p.Val1696Ala	missense_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152068 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000796 AC: 18 AN: 226244 Hom.: 0 AF XY: 0.0000571 AC XY: 7 AN XY: 122562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00105

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000174 AC: 25 AN: 1440138 Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 10 AN XY: 713684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000588

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74398

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000331 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2016

The V1707A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been reported in other individuals referred for inherited arrhythmia testing at GeneDx. The V1707A variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the V1707A variant has been reported in 4/3,384 (0.1%) alleles from individuals of East Asian ancestry in the Exome Aggregation Consortium. The V1707A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2018

The p.V1707A variant (also known as c.5120T>C), located in coding exon 42 of the CACNA1C gene, results from a T to C substitution at nucleotide position 5120. The valine at codon 1707 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.099	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	0.46	D
MutationAssessor	Uncertain	2.9	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.72
Sift	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.55	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.079, 0.73, 0.010, 1.0, 0.88, 0.99, 1.0, 0.99, 1.0, 0.98	.;D;B;P;B;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4		0.81
MutPred		0.43		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at H1754 (P = 6e-04);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.88
MPC		0.25
ClinPred		0.29	T
GERP RS		4.4
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs531161884; hg19: chr12-2788638;