rs2238092

Variant names:

• chr12-2614100-G-A
• rs2238092
• ENST00000480911.6:n.*4522G>A

Variant summary

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

The ENST00000480911.6(CACNA1C):​n.*4522G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 152,054 control chromosomes in the GnomAD database, including 33,668 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 0.64 (33662 hom., cov: 31)
  • Exomes 𝑓: 0.80 (6 hom.)
• Consequence: CACNA1C ENST00000480911.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.54
• Publications: 4 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3828+2087G>A		intron_variant	Intron 29 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3828+2087G>A		intron_variant	Intron 29 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000480911.6	n.*4522G>A		non_coding_transcript_exon_variant	Exon 27 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*4522G>A		3_prime_UTR_variant	Exon 27 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000399603.6	c.3828+2087G>A		intron_variant	Intron 29 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3828+2087G>A		intron_variant	Intron 29 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3978+2087G>A		intron_variant	Intron 30 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3828+2087G>A		intron_variant	Intron 29 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3828+2087G>A		intron_variant	Intron 29 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3993+2087G>A		intron_variant	Intron 30 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3888+2087G>A		intron_variant	Intron 30 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3828+2087G>A		intron_variant	Intron 29 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3828+2087G>A		intron_variant	Intron 29 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3828+2087G>A		intron_variant	Intron 29 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3918+2087G>A		intron_variant	Intron 29 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3918+2087G>A		intron_variant	Intron 29 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3918+2087G>A		intron_variant	Intron 29 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3918+2087G>A		intron_variant	Intron 29 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3828+2087G>A		intron_variant	Intron 29 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3903+2087G>A		intron_variant	Intron 30 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3888+2087G>A		intron_variant	Intron 30 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3828+2087G>A		intron_variant	Intron 29 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3828+2087G>A		intron_variant	Intron 29 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3828+2087G>A		intron_variant	Intron 29 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3828+2087G>A		intron_variant	Intron 29 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3903+2087G>A		intron_variant	Intron 30 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3828+2087G>A		intron_variant	Intron 29 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3828+2087G>A		intron_variant	Intron 29 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3828+2087G>A		intron_variant	Intron 29 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3828+2087G>A		intron_variant	Intron 29 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3828+2087G>A		intron_variant	Intron 29 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3828+2087G>A		intron_variant	Intron 29 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3828+2087G>A		intron_variant	Intron 29 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3828+2087G>A		intron_variant	Intron 29 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3819+2087G>A		intron_variant	Intron 29 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3828+2087G>A		intron_variant	Intron 29 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97396 AN: 151914 Hom.: 33654 Cov.: 31

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.644

GnomAD4 exome AF: 0.800 AC: 16 AN: 20 Hom.: 6 Cov.: 0 AF XY: 0.800 AC XY: 8 AN XY: 10

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.778 AC: 14 AN: 18

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000316713), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.641 AC: 97435 AN: 152034 Hom.: 33662 Cov.: 31 AF XY: 0.642 AC XY: 47679 AN XY: 74320

African (AFR) AF: 0.365 AC: 15109 AN: 41418

American (AMR) AF: 0.679 AC: 10370 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2448 AN: 3466

East Asian (EAS) AF: 0.654 AC: 3379 AN: 5168

South Asian (SAS) AF: 0.689 AC: 3319 AN: 4814

European-Finnish (FIN) AF: 0.769 AC: 8138 AN: 10582

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.772 AC: 52490 AN: 68000

Other (OTH) AF: 0.645 AC: 1359 AN: 2108

Alfa AF: 0.723 Hom.: 78533

Bravo AF: 0.624

Asia WGS AF: 0.694 AC: 2411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.049
DANN	Benign	0.63
PhyloP100		-2.5
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: rs2238092; hg19: chr12-2723266;