16-83990552-C-A

Variant names:

• chr16-83990552-C-A
• rs757750776
• NM_019065.3:c.518C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NECAB2 NM_019065.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.78

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]

ACMG classification

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 rank	MANE	Protein	UniProt
NECAB2	NM_019065.3	c.518C>A	p.Thr173Lys	missense_variant	Exon 6 of 13	ENST00000305202.9	NP_061938.2
NECAB2	NM_001329748.1	c.518C>A	p.Thr173Lys	missense_variant	Exon 6 of 12		NP_001316677.1
NECAB2	NM_001329749.2	c.269C>A	p.Thr90Lys	missense_variant	Exon 5 of 12		NP_001316678.1
NECAB2	XM_047434240.1	c.269C>A	p.Thr90Lys	missense_variant	Exon 5 of 12		XP_047290196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NECAB2	ENST00000305202.9	c.518C>A	p.Thr173Lys	missense_variant	Exon 6 of 13	1	NM_019065.3	ENSP00000307449.4
NECAB2	ENST00000565691.5	c.269C>A	p.Thr90Lys	missense_variant	Exon 4 of 11	1		ENSP00000457354.1
NECAB2	ENST00000566836.1	c.191C>A	p.Thr64Lys	missense_variant	Exon 4 of 7	5		ENSP00000455322.1
NECAB2	ENST00000681513.1	n.923C>A		non_coding_transcript_exon_variant	Exon 6 of 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

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

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

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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;.;.
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

Other links and lift over

dbSNP: rs757750776; hg19: chr16-84024157;