rs2283271

Variant names:

• chr12-2073132-T-A
• rs2283271
• NM_000719.7:c.49+19521T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000719.7(CACNA1C):​c.49+19521T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.763 in 152,054 control chromosomes in the GnomAD database, including 44,734 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (44734 hom., cov: 31)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.472
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.49+19521T>A		intron_variant	Intron 1 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.49+19521T>A		intron_variant	Intron 1 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.49+19521T>A		intron_variant	Intron 1 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.49+19521T>A		intron_variant	Intron 1 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.140-42092T>A		intron_variant	Intron 1 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.49+19521T>A		intron_variant	Intron 1 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.49+19521T>A		intron_variant	Intron 1 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.140-42092T>A		intron_variant	Intron 1 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.49+19521T>A		intron_variant	Intron 1 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.49+19521T>A		intron_variant	Intron 1 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.49+19521T>A		intron_variant	Intron 1 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.49+19521T>A		intron_variant	Intron 1 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.140-42092T>A		intron_variant	Intron 1 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.140-42092T>A		intron_variant	Intron 1 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.140-42092T>A		intron_variant	Intron 1 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.140-42092T>A		intron_variant	Intron 1 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.49+19521T>A		intron_variant	Intron 1 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.49+19521T>A		intron_variant	Intron 1 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.49+19521T>A		intron_variant	Intron 1 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.49+19521T>A		intron_variant	Intron 1 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.49+19521T>A		intron_variant	Intron 1 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.49+19521T>A		intron_variant	Intron 1 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.49+19521T>A		intron_variant	Intron 1 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.49+19521T>A		intron_variant	Intron 1 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.49+19521T>A		intron_variant	Intron 1 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.49+19521T>A		intron_variant	Intron 1 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.49+19521T>A		intron_variant	Intron 1 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.49+19521T>A		intron_variant	Intron 1 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.49+19521T>A		intron_variant	Intron 1 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.49+19521T>A		intron_variant	Intron 1 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.49+19521T>A		intron_variant	Intron 1 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.49+19521T>A		intron_variant	Intron 1 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.49+19521T>A		intron_variant	Intron 1 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.49+19521T>A		intron_variant	Intron 1 of 45			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.49+19521T>A		intron_variant	Intron 1 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.763 AC: 115943 AN: 151934 Hom.: 44685 Cov.: 31

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.825

Gnomad NFE AF: 0.775

Gnomad OTH AF: 0.770

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.763 AC: 116047 AN: 152054 Hom.: 44734 Cov.: 31 AF XY: 0.755 AC XY: 56080 AN XY: 74326

African (AFR) AF: 0.835 AC: 34651 AN: 41480

American (AMR) AF: 0.673 AC: 10284 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 2890 AN: 3470

East Asian (EAS) AF: 0.511 AC: 2635 AN: 5160

South Asian (SAS) AF: 0.664 AC: 3189 AN: 4806

European-Finnish (FIN) AF: 0.694 AC: 7341 AN: 10578

Middle Eastern (MID) AF: 0.829 AC: 242 AN: 292

European-Non Finnish (NFE) AF: 0.775 AC: 52660 AN: 67980

Other (OTH) AF: 0.772 AC: 1626 AN: 2106

Alfa AF: 0.769 Hom.: 5582

Bravo AF: 0.767

Asia WGS AF: 0.614 AC: 2137 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.89
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2283271; hg19: chr12-2182298;