rs200717140

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_000719.7(CACNA1C):c.2700G>A(p.Thr900Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,512 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. T900T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.322

Publications

1 publications found

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 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

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 12-2595910-G-A is Benign according to our data. Variant chr12-2595910-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 456957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.322 with no splicing effect.

BS2

High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.2790G>A	p.Thr930Thr	synonymous_variant	Exon 20 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.2865G>A	p.Thr955Thr	synonymous_variant	Exon 21 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.2790G>A	p.Thr930Thr	synonymous_variant	Exon 20 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.2790G>A	p.Thr930Thr	synonymous_variant	Exon 20 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.2790G>A	p.Thr930Thr	synonymous_variant	Exon 20 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.2790G>A	p.Thr930Thr	synonymous_variant	Exon 20 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.2775G>A	p.Thr925Thr	synonymous_variant	Exon 21 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.2775G>A	p.Thr925Thr	synonymous_variant	Exon 21 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.2691G>A	p.Thr897Thr	synonymous_variant	Exon 20 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.2700G>A	p.Thr900Thr	synonymous_variant	Exon 20 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1307G>A		non_coding_transcript_exon_variant	Exon 18 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*1307G>A		3_prime_UTR_variant	Exon 18 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000402

AC:

AN:

248998

AF XY:

0.0000518

show subpopulations

Gnomad AFR exome

AF:

0.0000646

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:

0.0000797

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461422

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

1111802

Other (OTH)

AF:

0.0000166

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000709

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 21, 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

-0.30

CADD

Benign

3.7

(source)

DANN

Benign

0.75

PhyloP100

-0.32

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over