20-33659661-C-T

Variant names:

• chr20-33659661-C-T
• rs749527745
• NM_031232.4:c.715G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031232.4(NECAB3):​c.715G>A​(p.Glu239Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,508 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NECAB3 NM_031232.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38

Genes affected

NECAB3 (HGNC:15851): (N-terminal EF-hand calcium binding protein 3) The protein encoded by this gene interacts with the amino-terminal domain of the neuron-specific X11-like protein (X11L), inhibits the association of X11L with amyloid precursor protein through a non-competitive mechanism, and abolishes the suppression of beta-amyloid production by X11L. This protein, together with X11L, may play an important role in the regulatory system of amyloid precursor protein metabolism and beta-amyloid generation. The protein is phosphorylated by NIMA-related expressed kinase 2, and localizes to the Golgi apparatus. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NECAB3	NM_031232.4	c.715G>A	p.Glu239Lys	missense_variant	Exon 8 of 12	ENST00000246190.11	NP_112509.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NECAB3	ENST00000246190.11	c.715G>A	p.Glu239Lys	missense_variant	Exon 8 of 12	5	NM_031232.4	ENSP00000246190.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000124 AC: 3 AN: 241052 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132436

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458508 Hom.: 0 Cov.: 33 AF XY: 0.00000827 AC XY: 6 AN XY: 725578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000256 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000830 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.715G>A (p.E239K) alteration is located in exon 8 (coding exon 8) of the NECAB3 gene. This alteration results from a G to A substitution at nucleotide position 715, causing the glutamic acid (E) at amino acid position 239 to be replaced by a lysine (K). 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	0.67
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;.;.;T;T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.0	M;M;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.6	D;D;.;.;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.78
MVP		0.42
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.78

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: rs749527745; hg19: chr20-32247467;