Variant 16-83990558-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_019065.3(NECAB2):c.524A>G(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 (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

NECAB2
NM_019065.3 missense

Scores

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]

NECAB2 links:

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
NECAB2	NM_019065.3 linkuse as main transcript	c.524A>G	p.Asn175Ser	missense_variant	6/13	ENST00000305202.9
NECAB2	NM_001329748.1 linkuse as main transcript	c.524A>G	p.Asn175Ser	missense_variant	6/12
NECAB2	NM_001329749.2 linkuse as main transcript	c.275A>G	p.Asn92Ser	missense_variant	5/12
NECAB2	XM_047434240.1 linkuse as main transcript	c.275A>G	p.Asn92Ser	missense_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NECAB2	ENST00000305202.9 linkuse as main transcript	c.524A>G	p.Asn175Ser	missense_variant	6/13	1	NM_019065.3	P1	Q7Z6G3-1
NECAB2	ENST00000565691.5 linkuse as main transcript	c.275A>G	p.Asn92Ser	missense_variant	4/11	1			Q7Z6G3-2
NECAB2	ENST00000566836.1 linkuse as main transcript	c.197A>G	p.Asn66Ser	missense_variant	4/7	5
NECAB2	ENST00000681513.1 linkuse as main transcript	n.929A>G		non_coding_transcript_exon_variant	6/13

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152144

Hom.:

Cov.:

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:

AN:

250538

Hom.:

AF XY:

0.0000443

AC XY:

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:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

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:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

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.:

Bravo

AF:

0.000382

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

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 submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The 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

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

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.027

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.

MutationTaster

Benign

0.80

D;N

PrimateAI

Benign

0.37

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

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.

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