12-2581611-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7

The NM_000719.7(CACNA1C):c.1917C>T(p.Asn639Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,417,586 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.24

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: 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=-0.33).

BP6

Variant 12-2581611-C-T is Benign according to our data. Variant chr12-2581611-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1029939.

BP7

Synonymous conserved (PhyloP=2.24 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 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.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.2007C>T	p.Asn669Asn	synonymous_variant	Exon 14 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.2082C>T	p.Asn694Asn	synonymous_variant	Exon 15 of 48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.2007C>T	p.Asn669Asn	synonymous_variant	Exon 14 of 47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.2007C>T	p.Asn669Asn	synonymous_variant	Exon 14 of 47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.2007C>T	p.Asn669Asn	synonymous_variant	Exon 14 of 47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.2007C>T	p.Asn669Asn	synonymous_variant	Exon 14 of 47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.1992C>T	p.Asn664Asn	synonymous_variant	Exon 15 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.1992C>T	p.Asn664Asn	synonymous_variant	Exon 15 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.1908C>T	p.Asn636Asn	synonymous_variant	Exon 14 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.1917C>T	p.Asn639Asn	synonymous_variant	Exon 14 of 46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.*524C>T		non_coding_transcript_exon_variant	Exon 12 of 27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000480911.6 link	n.*524C>T		3_prime_UTR_variant	Exon 12 of 27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1417586

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700684

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32430

American (AMR)

AF:

0.00

AC:

AN:

37926

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25336

East Asian (EAS)

AF:

0.00

AC:

AN:

37494

South Asian (SAS)

AF:

0.00

AC:

AN:

80364

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1088678

Other (OTH)

AF:

0.00

AC:

AN:

58866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Timothy syndrome

Uncertain:1

Nov 16, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Long QT syndrome

Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

9.8

(source)

DANN

Benign

0.73

PhyloP100

2.2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over