12-2648603-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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3945+96T>C		intron_variant	Intron 31 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3945+96T>C		intron_variant	Intron 31 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3945+96T>C		intron_variant	Intron 31 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3945+96T>C		intron_variant	Intron 31 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4179+96T>C		intron_variant	Intron 33 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3945+96T>C		intron_variant	Intron 31 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3913-3037T>C		intron_variant	Intron 30 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4110+96T>C		intron_variant	Intron 32 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4089+96T>C		intron_variant	Intron 33 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3945+96T>C		intron_variant	Intron 31 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3945+96T>C		intron_variant	Intron 31 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3945+96T>C		intron_variant	Intron 31 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4035+96T>C		intron_variant	Intron 31 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4035+96T>C		intron_variant	Intron 31 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4035+96T>C		intron_variant	Intron 31 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4035+96T>C		intron_variant	Intron 31 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4029+96T>C		intron_variant	Intron 32 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4020+96T>C		intron_variant	Intron 32 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4005+96T>C		intron_variant	Intron 32 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3945+96T>C		intron_variant	Intron 31 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3945+96T>C		intron_variant	Intron 31 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3945+96T>C		intron_variant	Intron 31 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3997-3037T>C		intron_variant	Intron 31 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3988-3037T>C		intron_variant	Intron 31 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3913-3037T>C		intron_variant	Intron 30 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3913-3037T>C		intron_variant	Intron 30 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3907-3037T>C		intron_variant	Intron 30 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3945+96T>C		intron_variant	Intron 31 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3945+96T>C		intron_variant	Intron 31 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3945+96T>C		intron_variant	Intron 31 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3945+96T>C		intron_variant	Intron 31 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3945+96T>C		intron_variant	Intron 31 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3936+96T>C		intron_variant	Intron 31 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3913-3037T>C		intron_variant	Intron 30 of 45			ENSP00000507309.1

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 v4.3

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;