NM_000719.7:c.828G>A

Variant names:

• chr12-2486174-G-A
• rs540934161
• NM_000719.7:c.828G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.828G>A​(p.Leu276Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,613,740 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.103
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-2486174-G-A is Benign according to our data. Variant chr12-2486174-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.103 with no splicing effect.
• 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.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.918G>A	p.Leu306Leu	synonymous_variant	Exon 6 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.918G>A	p.Leu306Leu	synonymous_variant	Exon 6 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.918G>A	p.Leu306Leu	synonymous_variant	Exon 6 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.918G>A	p.Leu306Leu	synonymous_variant	Exon 6 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.918G>A	p.Leu306Leu	synonymous_variant	Exon 6 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.918G>A	p.Leu306Leu	synonymous_variant	Exon 6 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.828G>A	p.Leu276Leu	synonymous_variant	Exon 6 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.777G>A	p.Leu259Leu	synonymous_variant	Exon 5 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.828G>A		non_coding_transcript_exon_variant	Exon 6 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000681 AC: 17 AN: 249668 AF XY: 0.0000740

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: 0.0000464

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1461572 Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 76 AN XY: 727074

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53402

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

European-Non Finnish (NFE) AF: 0.000136 AC: 151 AN: 1111774

Other (OTH) AF: 0.0000828 AC: 5 AN: 60362

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000416

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Apr 25, 2019

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_noAF	Benign	-0.56
CADD	Benign	3.6
DANN	Benign	0.79
PhyloP100		0.10

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

Other links and lift over

dbSNP: rs540934161; hg19: chr12-2595340;