16-83968707-C-A

Position:

• chr16-83968707-C-A

Variant summary

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

The NM_019065.3(NECAB2):​c.59C>A​(p.Pro20Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000814 in 860,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000081 (0 hom.)
• Consequence: NECAB2 NM_019065.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.428

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=0.06284258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NECAB2	NM_019065.3	c.59C>A	p.Pro20Gln	missense_variant	1/13	ENST00000305202.9
NECAB2	NM_001329748.1	c.59C>A	p.Pro20Gln	missense_variant	1/12
NECAB2	NM_001329749.2	c.-165C>A		5_prime_UTR_variant	1/12
NECAB2	XM_047434240.1	c.-22-3444C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NECAB2	ENST00000305202.9	c.59C>A	p.Pro20Gln	missense_variant	1/13	1	NM_019065.3	P1
NECAB2	ENST00000681513.1	n.464C>A		non_coding_transcript_exon_variant	1/13

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000814 AC: 7 AN: 860280 Hom.: 0 Cov.: 31 AF XY: 0.00000750 AC XY: 3 AN XY: 399890

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: 0.00000769

Gnomad4 OTH exome AF: 0.0000346

GnomAD4 genome Cov.: 30

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 04, 2023

The c.59C>A (p.P20Q) alteration is located in exon 1 (coding exon 1) of the NECAB2 gene. This alteration results from a C to A substitution at nucleotide position 59, causing the proline (P) at amino acid position 20 to be replaced by a glutamine (Q). 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	0.084
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.86	N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.021
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.028	D
Polyphen		0.024	B
Vest4		0.19
MutPred		0.31		Loss of catalytic residue at P20 (P = 5e-04);
MVP		0.067
ClinPred		0.23	T
GERP RS		0.32
Varity_R		0.079
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-84002312;