chr16-83990558-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_019065.3(NECAB2):ā€‹c.524A>Gā€‹(p.Asn175Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000917 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00035 ( 0 hom., cov: 32)
Exomes š‘“: 0.000064 ( 0 hom. )

Consequence

NECAB2
NM_019065.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.824
Variant links:
Genes affected
NECAB2 (HGNC:23746): (N-terminal EF-hand calcium binding protein 2) The protein encoded by this gene is a neuronal calcium-binding protein that binds to and modulates the function of at least two receptors, adenosine A(2A) receptor and metabotropic glutamate receptor type 5. [provided by RefSeq, Jul 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.027018964).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NECAB2NM_019065.3 linkuse as main transcriptc.524A>G p.Asn175Ser missense_variant 6/13 ENST00000305202.9
NECAB2NM_001329748.1 linkuse as main transcriptc.524A>G p.Asn175Ser missense_variant 6/12
NECAB2NM_001329749.2 linkuse as main transcriptc.275A>G p.Asn92Ser missense_variant 5/12
NECAB2XM_047434240.1 linkuse as main transcriptc.275A>G p.Asn92Ser missense_variant 5/12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NECAB2ENST00000305202.9 linkuse as main transcriptc.524A>G p.Asn175Ser missense_variant 6/131 NM_019065.3 P1Q7Z6G3-1
NECAB2ENST00000565691.5 linkuse as main transcriptc.275A>G p.Asn92Ser missense_variant 4/111 Q7Z6G3-2
NECAB2ENST00000566836.1 linkuse as main transcriptc.197A>G p.Asn66Ser missense_variant 4/75
NECAB2ENST00000681513.1 linkuse as main transcriptn.929A>G non_coding_transcript_exon_variant 6/13

Frequencies

GnomAD3 genomes
AF:
0.000355
AC:
54
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00123
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000758
AC:
19
AN:
250538
Hom.:
0
AF XY:
0.0000443
AC XY:
6
AN XY:
135466
show subpopulations
Gnomad AFR exome
AF:
0.000984
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000886
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000643
AC:
94
AN:
1461892
Hom.:
0
Cov.:
31
AF XY:
0.0000605
AC XY:
44
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00179
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000355
AC:
54
AN:
152144
Hom.:
0
Cov.:
32
AF XY:
0.000363
AC XY:
27
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.00123
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000898
Hom.:
0
Bravo
AF:
0.000382
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000906
AC:
11
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 GeneticsFeb 28, 2024The c.524A>G (p.N175S) alteration is located in exon 6 (coding exon 6) of the NECAB2 gene. This alteration results from a A to G substitution at nucleotide position 524, causing the asparagine (N) at amino acid position 175 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
0.051
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
7.2
DANN
Benign
0.65
DEOGEN2
Benign
0.040
T;.;T
Eigen
Benign
-0.98
Eigen_PC
Benign
-0.96
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.73
T;T;T
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.027
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L;.;.
MutationTaster
Benign
0.80
D;N
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-2.4
N;D;D
REVEL
Benign
0.10
Sift
Benign
0.37
T;T;T
Sift4G
Benign
0.34
T;T;T
Polyphen
0.010
B;.;.
Vest4
0.24
MVP
0.014
ClinPred
0.021
T
GERP RS
-4.4
Varity_R
0.046
gMVP
0.33

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: rs149674637; hg19: chr16-84024163; API