Genetic Variant CACNA1D:p.Asn2136Lys (chr3-53811268-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001128840.3(CACNA1D):c.6348C>G(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. 14/22 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 the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2116S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1D
NM_001128840.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.12

Publications

18 publications found

Variant links:

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]

CACNA1D Gene-Disease associations (from GenCC):

aldosterone-producing adenoma with seizures and neurological abnormalities
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
sinoatrial node dysfunction and deafness
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

CACNA1D links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2075296).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128840.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1D	NM_000720.4	MANE Plus Clinical	c.6408C>G	p.Asn2136Lys	missense	Exon 49 of 49	NP_000711.1	Q01668-2
CACNA1D	NM_001128840.3	MANE Select	c.6348C>G	p.Asn2116Lys	missense	Exon 48 of 48	NP_001122312.1	Q01668-1
CACNA1D	NM_001128839.3		c.6276C>G	p.Asn2092Lys	missense	Exon 46 of 46	NP_001122311.1	Q01668-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1D	ENST00000288139.11	TSL:1 MANE Plus Clinical	c.6408C>G	p.Asn2136Lys	missense	Exon 49 of 49	ENSP00000288139.3	Q01668-2
CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.6348C>G	p.Asn2116Lys	missense	Exon 48 of 48	ENSP00000288133.5	Q01668-1
CACNA1D	ENST00000481478.2	TSL:1	c.6408C>G	p.Asn2136Lys	missense	Exon 49 of 49	ENSP00000418014.2	H0Y879

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

8655

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.062

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.024

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.2

PhyloP100

-2.1

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.17

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.041

Polyphen

0.88

Vest4

0.30

MutPred

0.28

Gain of ubiquitination at N2116 (P = 0.0311)

MVP

0.70

MPC

0.52

ClinPred

0.96

GERP RS

-6.9

Varity_R

0.37

gMVP

0.56

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over