rs1455874684

Variant names:

• chr12-2651682-C-T
• rs1455874684
• NM_000719.7:c.3988C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.3988C>T​(p.Leu1330Leu) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,864 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L1330L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.90
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 12-2651682-C-T is Benign according to our data. Variant chr12-2651682-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 456969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000854 (13/152174) while in subpopulation AMR AF = 0.000851 (13/15280). AF 95% confidence interval is 0.000503. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4222C>T	p.Leu1408Leu	synonymous_variant	Exon 34 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3955C>T	p.Leu1319Leu	synonymous_variant	Exon 31 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4153C>T	p.Leu1385Leu	synonymous_variant	Exon 33 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4132C>T	p.Leu1378Leu	synonymous_variant	Exon 34 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4054C>T	p.Leu1352Leu	synonymous_variant	Exon 32 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4078C>T	p.Leu1360Leu	synonymous_variant	Exon 32 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4078C>T	p.Leu1360Leu	synonymous_variant	Exon 32 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4078C>T	p.Leu1360Leu	synonymous_variant	Exon 32 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4078C>T	p.Leu1360Leu	synonymous_variant	Exon 32 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4072C>T	p.Leu1358Leu	synonymous_variant	Exon 33 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4063C>T	p.Leu1355Leu	synonymous_variant	Exon 33 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4048C>T	p.Leu1350Leu	synonymous_variant	Exon 33 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4039C>T	p.Leu1347Leu	synonymous_variant	Exon 32 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4030C>T	p.Leu1344Leu	synonymous_variant	Exon 32 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3955C>T	p.Leu1319Leu	synonymous_variant	Exon 31 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3955C>T	p.Leu1319Leu	synonymous_variant	Exon 31 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3949C>T	p.Leu1317Leu	synonymous_variant	Exon 31 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 32 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3979C>T	p.Leu1327Leu	synonymous_variant	Exon 32 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3955C>T	p.Leu1319Leu	synonymous_variant	Exon 31 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152174 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 249542 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000144 AC: 21 AN: 1461690 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44722

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: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152174 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.000851 AC: 13 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000831

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:1

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Sep 15, 2021

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	-0.26
CADD	Benign	14
DANN	Benign	0.73
PhyloP100		7.9

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: rs1455874684; hg19: chr12-2760848;