12-2605553-C-T

Position:

chr12-2605553-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000719.7(CACNA1C):c.3049-126C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 710,236 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 18 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 4 hom. )

Consequence

CACNA1C
NM_000719.7 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.912

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 links:

CACNA1C-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

CACNA1C-AS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 12-2605553-C-T is Benign according to our data. Variant chr12-2605553-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 695530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00673 (1025/152232) while in subpopulation AFR AF= 0.0229 (952/41528). AF 95% confidence interval is 0.0217. There are 18 homozygotes in gnomad4. There are 496 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1025 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3049-126C>T		intron_variant		ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.3049-126C>T		intron_variant		ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.3049-126C>T	intron_variant	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.3049-126C>T	intron_variant	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.3199-126C>T	intron_variant			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.3049-126C>T	intron_variant	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.3049-126C>T	intron_variant	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.3214-126C>T	intron_variant			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.3109-126C>T	intron_variant	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.3049-126C>T	intron_variant	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.3049-126C>T	intron_variant	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.3049-126C>T	intron_variant	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.3139-126C>T	intron_variant			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.3139-126C>T	intron_variant			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.3139-126C>T	intron_variant			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.3139-126C>T	intron_variant			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.3049-126C>T	intron_variant	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.3124-126C>T	intron_variant	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.3109-126C>T	intron_variant	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.3049-126C>T	intron_variant	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.3049-126C>T	intron_variant	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.3049-126C>T	intron_variant	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.3049-126C>T	intron_variant	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.3124-126C>T	intron_variant			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.3049-126C>T	intron_variant	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.3049-126C>T	intron_variant	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.3049-126C>T	intron_variant	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.3049-126C>T	intron_variant	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.3049-126C>T	intron_variant	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.3049-126C>T	intron_variant	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.3049-126C>T	intron_variant	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.3049-126C>T	intron_variant			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.3040-126C>T	intron_variant			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.3049-126C>T	intron_variant			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.*1656-126C>T	intron_variant	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.00674

AC:

1025

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

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:

0.000176

Gnomad OTH

AF:

0.00576

GnomAD4 exome

AF:

0.000810

AC:

452

AN:

558004

Hom.:

AF XY:

0.000695

AC XY:

209

AN XY:

300812

show subpopulations

Gnomad4 AFR exome

AF:

0.0225

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000315

Gnomad4 SAS exome

AF:

0.000132

Gnomad4 FIN exome

AF:

0.0000219

Gnomad4 NFE exome

AF:

0.0000465

Gnomad4 OTH exome

AF:

0.00173

GnomAD4 genome

AF:

0.00673

AC:

1025

AN:

152232

Hom.:

Cov.:

AF XY:

0.00666

AC XY:

496

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0229

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00570

Alfa

AF:

0.0000704

Hom.:

Bravo

AF:

0.00785

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.35

DANN

Benign

0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over