12-2550654-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000719.7(CACNA1C):c.1481+621C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000334 in 1,196,764 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000033 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.236

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1481+621C>T		intron_variant	Intron 10 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1481+621C>T		intron_variant	Intron 10 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1481+621C>T	intron_variant	Intron 10 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1481+621C>T	intron_variant	Intron 10 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1571+621C>T	intron_variant	Intron 10 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1481+621C>T	intron_variant	Intron 10 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1481+621C>T	intron_variant	Intron 10 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1646+621C>T	intron_variant	Intron 11 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1481+621C>T	intron_variant	Intron 10 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1481+621C>T	intron_variant	Intron 10 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1481+621C>T	intron_variant	Intron 10 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1481+621C>T	intron_variant	Intron 10 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1571+621C>T	intron_variant	Intron 10 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1571+621C>T	intron_variant	Intron 10 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1571+621C>T	intron_variant	Intron 10 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1571+621C>T	intron_variant	Intron 10 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1481+621C>T	intron_variant	Intron 10 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1556+621C>T	intron_variant	Intron 11 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1481+621C>T	intron_variant	Intron 10 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1481+621C>T	intron_variant	Intron 10 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1481+621C>T	intron_variant	Intron 10 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1481+621C>T	intron_variant	Intron 10 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1481+621C>T	intron_variant	Intron 10 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1556+621C>T	intron_variant	Intron 11 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1481+621C>T	intron_variant	Intron 10 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1481+621C>T	intron_variant	Intron 10 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1481+621C>T	intron_variant	Intron 10 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1481+621C>T	intron_variant	Intron 10 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1481+621C>T	intron_variant	Intron 10 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1481+621C>T	intron_variant	Intron 10 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1481+621C>T	intron_variant	Intron 10 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1481+621C>T	intron_variant	Intron 10 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1472+621C>T	intron_variant	Intron 10 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1481+621C>T	intron_variant	Intron 10 of 45			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*88+621C>T	intron_variant	Intron 8 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000446

AC:

AN:

224016

AF XY:

0.00000809

show subpopulations

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000334

AC:

AN:

1196764

Hom.:

Cov.:

AF XY:

0.00000675

AC XY:

AN XY:

593024

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26252

American (AMR)

AF:

0.00

AC:

AN:

36966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16822

East Asian (EAS)

AF:

0.00

AC:

AN:

16760

South Asian (SAS)

AF:

0.0000486

AC:

AN:

82350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4106

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

952628

Other (OTH)

AF:

0.00

AC:

AN:

43790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.8

(source)

DANN

Benign

0.73

PhyloP100

-0.24

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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