12-2457567-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000719.7(CACNA1C):c.618G>T(p.Gly206Gly) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000137 in 1,458,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G206G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 splice_region, synonymous

Scores

Splicing: ADA: 0.9607

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.84

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:

ENSG00000285734 (HGNC:):

ENSG00000285734 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.708G>T	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.708G>T	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.708G>T	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.708G>T	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.708G>T	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.708G>T	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.618G>T	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.567G>T	p.Gly189Gly	splice_region_variant, synonymous_variant	Exon 4 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.618G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458608

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725518

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33304

American (AMR)

AF:

0.00

AC:

AN:

44304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39536

South Asian (SAS)

AF:

0.00

AC:

AN:

85660

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110452

Other (OTH)

AF:

0.00

AC:

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

6.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.75

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over