Variant 20-33659970-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_031232.4(NECAB3):c.558G>C(p.Arg186Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,564,466 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

NECAB3
NM_031232.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.522

Variant links:

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]

NECAB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043815285).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NECAB3	NM_031232.4 link	c.558G>C	p.Arg186Ser	missense_variant	7/12	ENST00000246190.11	NP_112509.3	Q96P71-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NECAB3	ENST00000246190.11 link	c.558G>C	p.Arg186Ser	missense_variant	7/12	5	NM_031232.4	ENSP00000246190.6		Q96P71-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000149

AC:

AN:

168344

Hom.:

AF XY:

0.000153

AC XY:

AN XY:

91708

show subpopulations

Gnomad AFR exome

AF:

0.000108

Gnomad AMR exome

AF:

0.0000384

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000408

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000300

Gnomad OTH exome

AF:

0.000220

GnomAD4 exome

AF:

0.000177

AC:

250

AN:

1412322

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

121

AN XY:

698662

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.0000270

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000223

Gnomad4 OTH exome

AF:

0.0000511

GnomAD4 genome

AF:

0.000145

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.000147

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000250

AC:

ExAC

AF:

0.000180

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 30, 2024

The c.558G>C (p.R186S) alteration is located in exon 7 (coding exon 7) of the NECAB3 gene. This alteration results from a G to C substitution at nucleotide position 558, causing the arginine (R) at amino acid position 186 to be replaced by a serine (S). 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

Benign

0.16

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.0

DANN

Benign

0.50

DEOGEN2

Benign

0.010

T;.;T;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.044

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;M;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.71

N;N;.;N

REVEL

Benign

0.12

Sift

Benign

0.68

T;T;.;T

Sift4G

Benign

0.86

T;T;.;.

Polyphen

0.0070

B;B;.;.

Vest4

0.24

MutPred

0.28

Loss of MoRF binding (P = 0.0196);Loss of MoRF binding (P = 0.0196);Loss of MoRF binding (P = 0.0196);Loss of MoRF binding (P = 0.0196);

MVP

0.28

MPC

0.36

ClinPred

0.027

GERP RS

3.0

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.13

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over