rs79398153

Variant names:

• chr12-2185990-C-T
• rs79398153
• NM_000719.7:c.477+65560C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.477+65560C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 152,272 control chromosomes in the GnomAD database, including 37 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 0.017 (37 hom., cov: 32)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.520
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• 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: ClinGen, Orphanet
• 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: ClinGen, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0168 (2558/152272) while in subpopulation AMR AF = 0.0352 (539/15296). AF 95% confidence interval is 0.0328. There are 37 homozygotes in GnomAd4. There are 1239 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2558 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.477+65560C>T		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.477+65560C>T		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.477+65560C>T		intron	N/A	NP_955630.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.477+65560C>T		intron	N/A	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.477+65560C>T		intron	N/A	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.567+65560C>T		intron	N/A	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2559 AN: 152154 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00567

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0168

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

GnomAD4 genome AF: 0.0168 AC: 2558 AN: 152272 Hom.: 37 Cov.: 32 AF XY: 0.0166 AC XY: 1239 AN XY: 74468

African (AFR) AF: 0.00565 AC: 235 AN: 41568

American (AMR) AF: 0.0352 AC: 539 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3468

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5178

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4824

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0202 AC: 1373 AN: 68000

Other (OTH) AF: 0.0166 AC: 35 AN: 2106

Alfa AF: 0.0183 Hom.: 8

Bravo AF: 0.0194

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.4
DANN	Benign	0.62
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism

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: rs79398153; hg19: chr12-2295156;