20-33659945-G-A

Variant summary

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

The NM_031232.4(NECAB3):​c.583C>T​(p.Arg195Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,554,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

NECAB3
NM_031232.4 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17
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]

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ACMG classification

Classification made for transcript

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/exons MANE Protein UniProt
NECAB3NM_031232.4 linkc.583C>T p.Arg195Cys missense_variant 7/12 ENST00000246190.11 NP_112509.3 Q96P71-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NECAB3ENST00000246190.11 linkc.583C>T p.Arg195Cys missense_variant 7/125 NM_031232.4 ENSP00000246190.6 Q96P71-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152166
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000258
AC:
4
AN:
154740
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
83962
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000797
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000163
Gnomad OTH exome
AF:
0.000231
GnomAD4 exome
AF:
0.00000856
AC:
12
AN:
1402678
Hom.:
0
Cov.:
33
AF XY:
0.00000433
AC XY:
3
AN XY:
692968
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000828
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000125
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000738
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152166
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000302

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 submitterclinical testingAmbry GeneticsDec 05, 2022The c.583C>T (p.R195C) alteration is located in exon 7 (coding exon 7) of the NECAB3 gene. This alteration results from a C to T substitution at nucleotide position 583, causing the arginine (R) at amino acid position 195 to be replaced by a cysteine (C). 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
0.20
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.24
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T;.;T;T
Eigen
Uncertain
0.31
Eigen_PC
Benign
0.16
FATHMM_MKL
Benign
0.52
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.46
T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Uncertain
2.9
M;M;.;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-5.4
D;D;.;D
REVEL
Benign
0.22
Sift
Uncertain
0.0010
D;D;.;D
Sift4G
Pathogenic
0.0010
D;D;.;.
Polyphen
1.0
D;D;.;.
Vest4
0.20
MVP
0.32
MPC
1.2
ClinPred
0.95
D
GERP RS
4.1
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.42
gMVP
0.52

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

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

Other links and lift over

dbSNP: rs1234521299; hg19: chr20-32247751; COSMIC: COSV55778868; COSMIC: COSV55778868; API