rs10154841

chr3-53811268-C-Gchr3-53811268-C-T

Variant summary

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

The NM_000720.4(CACNA1D):c.6408C>G(p.Asn2136Lys) 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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2136S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1D NM_000720.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 where missense usually causes diseases, CACNA1D
• BP4: Computational evidence support a benign effect (MetaRNN=0.2075296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.6408C>G	p.Asn2136Lys	missense_variant	49/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.6348C>G	p.Asn2116Lys	missense_variant	48/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.6408C>G	p.Asn2136Lys	missense_variant	49/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.6348C>G	p.Asn2116Lys	missense_variant	48/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

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	0.062
Dann	Uncertain	0.98
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	0.024	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	0.99	P;P;P;P
PrimateAI	Benign	0.46	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		0.96	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

LitVar

Other links and lift over

dbSNP: rs10154841; hg19: chr3-53845295;