rs146892408

Positions:

• chr3-53749314-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_001128840.3(CACNA1D):​c.3361A>G​(p.Ile1121Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.818

Genes affected

CACNA1D (HGNC:1391): (calcium voltage-gated channel subunit alpha1 D) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, namely alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1D subunit. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1D. . Gene score misZ 4.5817 (greater than the threshold 3.09). Trascript score misZ 6.6073 (greater than threshold 3.09). GenCC has associacion of gene with sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010209113).
• BP6: Variant 3-53749314-A-G is Benign according to our data. Variant chr3-53749314-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 227200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000282 (43/152262) while in subpopulation SAS AF= 0.00125 (6/4816). AF 95% confidence interval is 0.000542. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.3421A>G	p.Ile1141Val	missense_variant	28/49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.3361A>G	p.Ile1121Val	missense_variant	27/48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.3421A>G	p.Ile1141Val	missense_variant	28/49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.3361A>G	p.Ile1121Val	missense_variant	27/48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000676 AC: 170 AN: 251414 Hom.: 0 AF XY: 0.000692 AC XY: 94 AN XY: 135902

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00714

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000452 AC: 660 AN: 1461794 Hom.: 0 Cov.: 30 AF XY: 0.000487 AC XY: 354 AN XY: 727222

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00681

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000274

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74462

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000634 Hom.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000502 AC: 61

EpiCase AF: 0.000382

EpiControl AF: 0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 24, 2017

p.Ile1141Val in exon 28 of CACNA1D: This variant is not expected to have clinica l significance due to a lack of conservation across species, including mammals. Of note, 10 different mammals have a valine (Val) at this position despite high nearby amino acid sequence conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. This variant h as been identified in 0.7% (75/10152) Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1468924 08). -

Aldosterone-producing adenoma with seizures and neurological abnormalities Benign:1

Likely benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CACNA1D-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	1.9
DANN	Benign	0.78
DEOGEN2	Uncertain	0.43	.;T;.;.;.;.;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.76	T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.010	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	0.44	.;N;.;.;.;N;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.60	.;N;.;.;N;N;.;.;N
REVEL	Benign	0.27
Sift	Benign	0.27	.;T;.;.;T;T;.;.;T
Sift4G	Benign	0.22	.;T;.;.;T;T;.;.;T
Polyphen		0.0, 0.0010	.;B;.;B;B;.;.;.;B
Vest4		0.14, 0.14, 0.14
MVP		0.43
MPC		0.67
ClinPred		0.0025	T
GERP RS		1.3
Varity_R		0.042
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs146892408; hg19: chr3-53783341;