12-2601850-G-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.2854-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 splice_region, intron

Scores

Splicing: ADA: 0.000005277

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.617

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=-0.59).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.2854-4G>T		splice_region_variant, intron_variant	Intron 21 of 46	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.2854-4G>T		splice_region_variant, intron_variant	Intron 21 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.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.3004-4G>T	splice_region_variant, intron_variant	Intron 22 of 49			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 47	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.3019-4G>T	splice_region_variant, intron_variant	Intron 22 of 47			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.2914-4G>T	splice_region_variant, intron_variant	Intron 22 of 48	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 47	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 47	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.2944-4G>T	splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.2944-4G>T	splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.2944-4G>T	splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.2944-4G>T	splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 47	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.2929-4G>T	splice_region_variant, intron_variant	Intron 22 of 47	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.2914-4G>T	splice_region_variant, intron_variant	Intron 22 of 47	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.2929-4G>T	splice_region_variant, intron_variant	Intron 22 of 46			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 45	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 45	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 45	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.2845-4G>T	splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.2854-4G>T	splice_region_variant, intron_variant	Intron 21 of 45			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.*1461-4G>T	splice_region_variant, intron_variant	Intron 19 of 26	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1453738

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33292

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.00

AC:

AN:

86086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1104724

Other (OTH)

AF:

0.00

AC:

AN:

60058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

-0.59

CADD

Benign

(source)

DANN

Benign

0.55

PhyloP100

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000053

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.020

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