chr16-83990531-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_019065.3(NECAB2):​c.497C>T​(p.Thr166Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

NECAB2
NM_019065.3 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.78
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NECAB2NM_019065.3 linkuse as main transcriptc.497C>T p.Thr166Ile missense_variant 6/13 ENST00000305202.9
NECAB2NM_001329748.1 linkuse as main transcriptc.497C>T p.Thr166Ile missense_variant 6/12
NECAB2NM_001329749.2 linkuse as main transcriptc.248C>T p.Thr83Ile missense_variant 5/12
NECAB2XM_047434240.1 linkuse as main transcriptc.248C>T p.Thr83Ile missense_variant 5/12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NECAB2ENST00000305202.9 linkuse as main transcriptc.497C>T p.Thr166Ile missense_variant 6/131 NM_019065.3 P1Q7Z6G3-1
NECAB2ENST00000565691.5 linkuse as main transcriptc.248C>T p.Thr83Ile missense_variant 4/111 Q7Z6G3-2
NECAB2ENST00000566836.1 linkuse as main transcriptc.170C>T p.Thr57Ile missense_variant 4/75
NECAB2ENST00000681513.1 linkuse as main transcriptn.902C>T non_coding_transcript_exon_variant 6/13

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152128
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.00633
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000479
AC:
12
AN:
250376
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135378
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000289
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:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000246
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152246
Hom.:
0
Cov.:
32
AF XY:
0.0000806
AC XY:
6
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.0000481
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000102
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

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 GeneticsJan 23, 2024The c.497C>T (p.T166I) alteration is located in exon 6 (coding exon 6) of the NECAB2 gene. This alteration results from a C to T substitution at nucleotide position 497, causing the threonine (T) at amino acid position 166 to be replaced by an isoleucine (I). 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
0.85
BayesDel_addAF
Uncertain
0.074
D
BayesDel_noAF
Pathogenic
0.17
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.48
T;.;T
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.89
D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.76
D;D;D
MetaSVM
Benign
-0.54
T
MutationAssessor
Pathogenic
3.0
M;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.0
D;D;D
REVEL
Uncertain
0.62
Sift
Uncertain
0.0040
D;D;D
Sift4G
Uncertain
0.0080
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.97
MutPred
0.69
Gain of ubiquitination at K171 (P = 0.1062);.;.;
MVP
0.29
ClinPred
0.91
D
GERP RS
5.1
Varity_R
0.59
gMVP
0.71

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: rs763808340; hg19: chr16-84024136; API