CACNA1C p.Asp1334Asn

Variant names:

• chr12-2651628-G-A
• rs41276706
• ENST00000344100.7:c.4000G>A
• CACNA1C p.Asp1334Asn

Your query was ambiguous. Multiple possible variants found:

• chr12-2651628-G-A
• chr12-2651628-GAC-AAT

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001129829.2(CACNA1C):​c.4000G>A​(p.Asp1334Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000305 in 1,613,770 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1334E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: CACNA1C NM_001129829.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -0.200
• Publications: 6 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, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041235715).
• BP6: Variant 12-2651628-G-A is Benign according to our data. Variant chr12-2651628-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190617.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000315 (461/1461672) while in subpopulation SAS AF = 0.000765 (66/86256). AF 95% confidence interval is 0.000616. There are 2 homozygotes in GnomAdExome4. There are 237 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 32 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001129829.2. 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.3946-12G>A		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.3946-12G>A		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_001129829.2		c.4000G>A	p.Asp1334Asn	missense	Exon 32 of 47	NP_001123301.1	Q13936-14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000344100.7	TSL:1	c.4000G>A	p.Asp1334Asn	missense	Exon 32 of 47	ENSP00000341092.3	Q13936-14
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.3946-12G>A		intron	N/A	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.3946-12G>A		intron	N/A	ENSP00000382563.1	Q13936-12

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152098 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000233 AC: 58 AN: 249296 AF XY: 0.000311

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000315 AC: 461 AN: 1461672 Hom.: 2 Cov.: 33 AF XY: 0.000326 AC XY: 237 AN XY: 727126

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 17 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000765 AC: 66 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000317 AC: 353 AN: 1111856

Other (OTH) AF: 0.000265 AC: 16 AN: 60374

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152098 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74282

African (AFR) AF: 0.000169 AC: 7 AN: 41422

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.000215

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	-	2	not specified (2)
-	-	1	CACNA1C-related disorder (1)
-	-	1	Intellectual disability (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.3
DANN	Uncertain	0.97
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.17	N
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.28	T
PhyloP100		-0.20
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.27
Sift	Benign	0.16	T
Sift4G	Benign	0.34	T
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41276706;

hg19: chr12-2760794;