rs553958501

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000719.7(CACNA1C):c.960G>A(p.Thr320Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,613,992 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000072 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 2 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.25

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 12-2493233-G-A is Benign according to our data. Variant chr12-2493233-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000722 (11/152322) while in subpopulation SAS AF= 0.00124 (6/4824). AF 95% confidence interval is 0.000541. There are 1 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.1050G>A	p.Thr350Thr	synonymous_variant	Exon 7 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.1050G>A	p.Thr350Thr	synonymous_variant	Exon 7 of 48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.1050G>A	p.Thr350Thr	synonymous_variant	Exon 7 of 47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.1050G>A	p.Thr350Thr	synonymous_variant	Exon 7 of 47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.1050G>A	p.Thr350Thr	synonymous_variant	Exon 7 of 47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.1050G>A	p.Thr350Thr	synonymous_variant	Exon 7 of 47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.951G>A	p.Thr317Thr	synonymous_variant	Exon 7 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.960G>A	p.Thr320Thr	synonymous_variant	Exon 7 of 46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000682152.1 link	c.897G>A	p.Thr299Thr	synonymous_variant	Exon 6 of 6			ENSP00000506759.1	A0A804HHT8
CACNA1C	ENST00000480911.6 link	n.960G>A		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000241

AC:

AN:

248944

Hom.:

AF XY:

0.000318

AC XY:

AN XY:

135070

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00193

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000145

AC:

212

AN:

1461670

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

153

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00224

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000756

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 29, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome

Benign:1

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 15, 2018

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

-0.93

CADD

Benign

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.47

Position offset: 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