chr16-83990552-C-A

Variant summary

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

The NM_019065.3(NECAB2):​c.518C>A​(p.Thr173Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,884 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T173M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 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, 0.797

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NECAB2NM_019065.3 linkuse as main transcriptc.518C>A p.Thr173Lys missense_variant 6/13 ENST00000305202.9
NECAB2NM_001329748.1 linkuse as main transcriptc.518C>A p.Thr173Lys missense_variant 6/12
NECAB2NM_001329749.2 linkuse as main transcriptc.269C>A p.Thr90Lys missense_variant 5/12
NECAB2XM_047434240.1 linkuse as main transcriptc.269C>A p.Thr90Lys missense_variant 5/12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NECAB2ENST00000305202.9 linkuse as main transcriptc.518C>A p.Thr173Lys missense_variant 6/131 NM_019065.3 P1Q7Z6G3-1
NECAB2ENST00000565691.5 linkuse as main transcriptc.269C>A p.Thr90Lys missense_variant 4/111 Q7Z6G3-2
NECAB2ENST00000566836.1 linkuse as main transcriptc.191C>A p.Thr64Lys missense_variant 4/75
NECAB2ENST00000681513.1 linkuse as main transcriptn.923C>A non_coding_transcript_exon_variant 6/13

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250512
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135458
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000886
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461884
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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 03, 2024The c.518C>A (p.T173K) alteration is located in exon 6 (coding exon 6) of the NECAB2 gene. This alteration results from a C to A substitution at nucleotide position 518, causing the threonine (T) at amino acid position 173 to be replaced by a lysine (K). 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
0.99
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.46
T;.;T
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.80
D;D;D
MetaSVM
Benign
-0.70
T
MutationAssessor
Pathogenic
3.0
M;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-4.8
D;D;D
REVEL
Uncertain
0.43
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.77
MutPred
0.57
Gain of ubiquitination at T173 (P = 0.03);.;.;
MVP
0.23
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.81
gMVP
0.65

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: rs757750776; hg19: chr16-84024157; API