16-83968772-C-T

Position:

• chr16-83968772-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001329749.2(NECAB2):​c.-100C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000147 in 953,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: NECAB2 NM_001329749.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.195

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 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=0.06382471).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NECAB2	NM_019065.3	c.124C>T	p.Arg42Trp	missense_variant	1/13	ENST00000305202.9	NP_061938.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NECAB2	ENST00000305202.9	c.124C>T	p.Arg42Trp	missense_variant	1/13	1	NM_019065.3	ENSP00000307449.4
NECAB2	ENST00000681513.1	n.529C>T		non_coding_transcript_exon_variant	1/13

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000147 AC: 14 AN: 953016 Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 6 AN XY: 448054

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: 0.0000167

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2024

The c.124C>T (p.R42W) alteration is located in exon 1 (coding exon 1) of the NECAB2 gene. This alteration results from a C to T substitution at nucleotide position 124, causing the arginine (R) at amino acid position 42 to be replaced by a tryptophan (W). 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	0.59
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0093	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.028
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.043	B
Vest4		0.15
MutPred		0.29		Gain of catalytic residue at R42 (P = 0.0086);
MVP		0.099
ClinPred		0.35	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.077
gMVP		0.37

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: rs2084317290; hg19: chr16-84002377;