chr12-2648603-T-C

Variant names:

• chr12-2648603-T-C
• rs2239128
• NM_000719.7:c.3945+96T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000719.7(CACNA1C):​c.3945+96T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,073,460 control chromosomes in the GnomAD database, including 322,910 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39315 hom., cov: 29)
  • Exomes 𝑓: 0.78 (283595 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00500
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-2648603-T-C is Benign according to our data. Variant chr12-2648603-T-C is described in ClinVar as Benign. ClinVar VariationId is 671807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.3945+96T>C		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.3945+96T>C		intron	N/A	NP_001161095.1
	CACNA1C	NM_199460.4		c.4089+96T>C		intron	N/A	NP_955630.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.3945+96T>C		intron	N/A	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.3945+96T>C		intron	N/A	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.4179+96T>C		intron	N/A	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.707 AC: 106958 AN: 151320 Hom.: 39288 Cov.: 29

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.663

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.755

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.841

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.701

GnomAD4 exome AF: 0.781 AC: 719652 AN: 922022 Hom.: 283595 AF XY: 0.778 AC XY: 373731 AN XY: 480144

African (AFR) AF: 0.479 AC: 11112 AN: 23180

American (AMR) AF: 0.864 AC: 37413 AN: 43318

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 16685 AN: 22324

East Asian (EAS) AF: 0.701 AC: 26003 AN: 37106

South Asian (SAS) AF: 0.714 AC: 53094 AN: 74320

European-Finnish (FIN) AF: 0.834 AC: 42956 AN: 51486

Middle Eastern (MID) AF: 0.596 AC: 2579 AN: 4324

European-Non Finnish (NFE) AF: 0.799 AC: 497840 AN: 623438

Other (OTH) AF: 0.752 AC: 31970 AN: 42526

GnomAD4 genome AF: 0.707 AC: 107021 AN: 151438 Hom.: 39315 Cov.: 29 AF XY: 0.708 AC XY: 52395 AN XY: 73956

African (AFR) AF: 0.490 AC: 20150 AN: 41150

American (AMR) AF: 0.800 AC: 12208 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.755 AC: 2614 AN: 3462

East Asian (EAS) AF: 0.670 AC: 3418 AN: 5102

South Asian (SAS) AF: 0.712 AC: 3401 AN: 4776

European-Finnish (FIN) AF: 0.841 AC: 8818 AN: 10490

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.798 AC: 54157 AN: 67906

Other (OTH) AF: 0.701 AC: 1470 AN: 2096

Alfa AF: 0.755 Hom.: 64455

Bravo AF: 0.693

Asia WGS AF: 0.702 AC: 2440 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Timothy syndrome Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Long QT syndrome Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.25
DANN	Benign	0.31
PhyloP100		-0.0050
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: rs2239128; hg19: chr12-2757769; COSMIC: COSV59724798; COSMIC: COSV59724798;