rs747320984

Variant names:

• chr12-2449113-G-A
• rs747320984
• NM_000719.7:c.615G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2449113-G-A
• chr12-2449113-G-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.615G>A​(p.Val205Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000432 in 1,390,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V205V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: CACNA1C NM_000719.7 splice_region, synonymous
• Scores: Splicing: ADA: 0.00002144
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.65
• Publications: 1 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

ENSG00000285734 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 12-2449113-G-A is Benign according to our data. Variant chr12-2449113-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 672193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.65 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.705G>A	p.Val235Val	splice_region_variant, synonymous_variant	Exon 4 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.705G>A	p.Val235Val	splice_region_variant, synonymous_variant	Exon 4 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.705G>A	p.Val235Val	splice_region_variant, synonymous_variant	Exon 4 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.705G>A	p.Val235Val	splice_region_variant, synonymous_variant	Exon 4 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.705G>A	p.Val235Val	splice_region_variant, synonymous_variant	Exon 4 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.705G>A	p.Val235Val	splice_region_variant, synonymous_variant	Exon 4 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.615G>A	p.Val205Val	splice_region_variant, synonymous_variant	Exon 4 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.564G>A	p.Val188Val	splice_region_variant, synonymous_variant	Exon 3 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.615G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000651 AC: 1 AN: 153602 AF XY: 0.0000125

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: 0.0000160

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000432 AC: 6 AN: 1390178 Hom.: 0 Cov.: 30 AF XY: 0.00000584 AC XY: 4 AN XY: 685096

African (AFR) AF: 0.00 AC: 0 AN: 31178

American (AMR) AF: 0.00 AC: 0 AN: 33076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24766

East Asian (EAS) AF: 0.00 AC: 0 AN: 36658

South Asian (SAS) AF: 0.00 AC: 0 AN: 75964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00000465 AC: 5 AN: 1075314

Other (OTH) AF: 0.0000173 AC: 1 AN: 57732

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Jun 18, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Long QT syndrome Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.91
PhyloP100		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0080
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: rs747320984; hg19: chr12-2558279;