12-2668924-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000719.7(CACNA1C):c.4624-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,604,908 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

CACNA1C
NM_000719.7 intron

Scores

Splicing: ADA: 0.001406

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.273

Variant links:

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 links:

CACNA1C-AS2 (HGNC:):

CACNA1C-AS2 links:

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

CACNA1C-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 12-2668924-C-T is Benign according to our data. Variant chr12-2668924-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2668924-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00149 (227/152330) while in subpopulation AFR AF= 0.00522 (217/41578). AF 95% confidence interval is 0.00465. There are 1 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 227 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.4624-9C>T		intron_variant	Intron 37 of 46	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.4624-9C>T		intron_variant	Intron 37 of 46	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.4624-9C>T	intron_variant	Intron 37 of 46	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.4624-9C>T	intron_variant	Intron 37 of 46	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.4858-9C>T	intron_variant	Intron 39 of 49			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.4624-9C>T	intron_variant	Intron 37 of 47	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.4591-9C>T	intron_variant	Intron 36 of 46	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.4789-9C>T	intron_variant	Intron 38 of 47			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.4768-9C>T	intron_variant	Intron 39 of 48	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.4690-9C>T	intron_variant	Intron 37 of 46	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.4624-9C>T	intron_variant	Intron 37 of 47	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.4624-9C>T	intron_variant	Intron 37 of 47	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.4714-9C>T	intron_variant	Intron 37 of 46			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.4714-9C>T	intron_variant	Intron 37 of 46			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.4714-9C>T	intron_variant	Intron 37 of 46			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.4714-9C>T	intron_variant	Intron 37 of 46			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.4708-9C>T	intron_variant	Intron 38 of 47	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.4699-9C>T	intron_variant	Intron 38 of 47	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.4684-9C>T	intron_variant	Intron 38 of 47	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.4624-9C>T	intron_variant	Intron 37 of 46	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.4624-9C>T	intron_variant	Intron 37 of 46	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.4624-9C>T	intron_variant	Intron 37 of 46	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.4675-9C>T	intron_variant	Intron 37 of 46	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.4666-9C>T	intron_variant	Intron 37 of 46			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.4591-9C>T	intron_variant	Intron 36 of 45	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.4591-9C>T	intron_variant	Intron 36 of 45	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.4585-9C>T	intron_variant	Intron 36 of 45	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.4624-9C>T	intron_variant	Intron 37 of 46	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.4624-9C>T	intron_variant	Intron 37 of 46	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.4624-9C>T	intron_variant	Intron 37 of 46	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.4624-9C>T	intron_variant	Intron 37 of 46	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.4624-9C>T	intron_variant	Intron 37 of 46			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.4615-9C>T	intron_variant	Intron 37 of 46			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.4591-9C>T	intron_variant	Intron 36 of 45			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

226

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00521

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000364

AC:

AN:

250094

Hom.:

AF XY:

0.000310

AC XY:

AN XY:

135510

show subpopulations

Gnomad AFR exome

AF:

0.00503

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000219

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000150

AC:

218

AN:

1452578

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

723344

show subpopulations

Gnomad4 AFR exome

AF:

0.00499

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000163

Gnomad4 OTH exome

AF:

0.000266

GnomAD4 genome

AF:

0.00149

AC:

227

AN:

152330

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00522

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.00143

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 06, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2013

GeneDx

Significance: 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. -

not provided

Benign:2

Sep 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: BS1 -

Long QT syndrome

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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

-0.67

CADD

Benign

DANN

Benign

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0014

dbscSNV1_RF

Benign

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over