chr12-2679496-G-A

Variant names:

• chr12-2679496-G-A
• rs376706496
• NM_000719.7:c.5144G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS2

The NM_000719.7(CACNA1C):​c.5144G>A​(p.Arg1715Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,607,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.14

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-AS1 (HGNC:):

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

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• BP6: Variant 12-2679496-G-A is Benign according to our data. Variant chr12-2679496-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190685.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5378G>A	p.Arg1793Gln	missense_variant	Exon 44 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5111G>A	p.Arg1704Gln	missense_variant	Exon 41 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5309G>A	p.Arg1770Gln	missense_variant	Exon 43 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5288G>A	p.Arg1763Gln	missense_variant	Exon 44 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5267G>A	p.Arg1756Gln	missense_variant	Exon 42 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5234G>A	p.Arg1745Gln	missense_variant	Exon 42 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5234G>A	p.Arg1745Gln	missense_variant	Exon 42 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5234G>A	p.Arg1745Gln	missense_variant	Exon 42 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5234G>A	p.Arg1745Gln	missense_variant	Exon 42 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5228G>A	p.Arg1743Gln	missense_variant	Exon 43 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5219G>A	p.Arg1740Gln	missense_variant	Exon 43 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5204G>A	p.Arg1735Gln	missense_variant	Exon 43 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5201G>A	p.Arg1734Gln	missense_variant	Exon 42 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5201G>A	p.Arg1734Gln	missense_variant	Exon 42 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5201G>A	p.Arg1734Gln	missense_variant	Exon 42 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5195G>A	p.Arg1732Gln	missense_variant	Exon 42 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5186G>A	p.Arg1729Gln	missense_variant	Exon 42 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5168G>A	p.Arg1723Gln	missense_variant	Exon 41 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5168G>A	p.Arg1723Gln	missense_variant	Exon 41 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5162G>A	p.Arg1721Gln	missense_variant	Exon 41 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5144G>A	p.Arg1715Gln	missense_variant	Exon 42 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5135G>A	p.Arg1712Gln	missense_variant	Exon 42 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5111G>A	p.Arg1704Gln	missense_variant	Exon 41 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152148 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000166 AC: 4 AN: 241542 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131280

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 SAS exome AF: 0.0000999

Gnomad FIN exome AF: 0.0000479

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000213 AC: 31 AN: 1455144 Hom.: 0 Cov.: 31 AF XY: 0.0000180 AC XY: 13 AN XY: 722932

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000700

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000199

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Nov 29, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R1715Q 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 observed in one other unrelated individual referred for Brugada syndrome genetic testing at GeneDx. This variant was not observed at a significant frequency 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. The R1715Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. 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. However, to our knowledge no studies have been performed to determine the functional effect of the R1715Q variant.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -

Long QT syndrome Benign:1

Apr 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 16, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.1	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D;D;D;D;D;D;D;D;N;D;D;D;D;N;D;D;.
REVEL	Uncertain	0.62
Sift	Benign	0.063	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;D;D;D;.
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.95, 0.053, 0.33, 0.092, 0.98, 0.98, 0.97, 0.12, 0.97, 0.97, 1.0, 0.98	.;P;B;B;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;P;.
Vest4		0.50
MVP		0.89
MPC		0.25
ClinPred		0.62	D
GERP RS		4.6
gMVP		0.50

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: rs376706496; hg19: chr12-2788662; COSMIC: COSV104647457; COSMIC: COSV104647457;