chr3-54123552-A-C

Position:

• chr3-54123552-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018398.3(CACNA2D3):​c.162A>C​(p.Lys54Asn) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA2D3 NM_018398.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

Genes affected

CACNA2D3 (HGNC:15460): (calcium voltage-gated channel auxiliary subunit alpha2delta 3) This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28853363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D3	NM_018398.3	c.162A>C	p.Lys54Asn	missense_variant	2/38	ENST00000474759.6	NP_060868.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D3	ENST00000474759.6	c.162A>C	p.Lys54Asn	missense_variant	2/38	1	NM_018398.3	ENSP00000419101	P1
	ENST00000666932.1	n.692T>G		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2023

The c.162A>C (p.K54N) alteration is located in exon 2 (coding exon 2) of the CACNA2D3 gene. This alteration results from a A to C substitution at nucleotide position 162, causing the lysine (K) at amino acid position 54 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	.;D;.
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L;L
MutationTaster	Benign	0.72	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.45	N;N;N
REVEL	Benign	0.048
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0070	B;B;B
Vest4		0.63
MutPred		0.46		Loss of ubiquitination at K54 (P = 0.0233);Loss of ubiquitination at K54 (P = 0.0233);Loss of ubiquitination at K54 (P = 0.0233);
MVP		0.043
MPC		0.50
ClinPred		0.47	T
GERP RS		4.7
Varity_R		0.11
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr3-54157579;