rs10154841

Variant names:

• chr3-53811268-C-A
• NM_000720.4:c.6408C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-53811268-C-A
• chr3-53811268-C-G
• chr3-53811268-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001128840.3(CACNA1D):​c.6348C>A​(p.Asn2116Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N2116N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.12

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CACNA1D gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 27 curated benign missense variants. Gene score misZ: 4.5817 (above the threshold of 3.09). Trascript score misZ: 6.6073 (above the threshold of 3.09). GenCC associations: The gene is linked to sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20783794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.6408C>A	p.Asn2136Lys	missense_variant	Exon 49 of 49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.6348C>A	p.Asn2116Lys	missense_variant	Exon 48 of 48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.6408C>A	p.Asn2136Lys	missense_variant	Exon 49 of 49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.6348C>A	p.Asn2116Lys	missense_variant	Exon 48 of 48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2136 of the CACNA1D protein (p.Asn2136Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.051
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;T;.;.;.;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.86	D;D;.;D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.2	.;M;.;.;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.0	.;D;.;D;D;.;D
REVEL	Benign	0.17
Sift	Uncertain	0.0050	.;D;.;D;D;.;D
Sift4G	Uncertain	0.041	.;D;.;D;D;.;T
Polyphen		0.88, 0.96, 0.63	.;P;D;D;.;.;P
Vest4		0.30, 0.32, 0.39
MutPred		0.28		.;Gain of ubiquitination at N2116 (P = 0.0311);.;.;.;.;.;
MVP		0.70
MPC		0.52
ClinPred		0.97	D
GERP RS		-6.9
Varity_R		0.37
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-53845295;