20-33659696-T-C

Variant names:

• chr20-33659696-T-C
• rs1255816144
• NM_031232.4:c.680A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031232.4(NECAB3):​c.680A>G​(p.Gln227Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000757 in 1,453,216 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: NECAB3 NM_031232.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.29

Genes affected

NECAB3 (HGNC:15851): (N-terminal EF-hand calcium binding protein 3) The protein encoded by this gene interacts with the amino-terminal domain of the neuron-specific X11-like protein (X11L), inhibits the association of X11L with amyloid precursor protein through a non-competitive mechanism, and abolishes the suppression of beta-amyloid production by X11L. This protein, together with X11L, may play an important role in the regulatory system of amyloid precursor protein metabolism and beta-amyloid generation. The protein is phosphorylated by NIMA-related expressed kinase 2, and localizes to the Golgi apparatus. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NECAB3	NM_031232.4	c.680A>G	p.Gln227Arg	missense_variant	Exon 8 of 12	ENST00000246190.11	NP_112509.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NECAB3	ENST00000246190.11	c.680A>G	p.Gln227Arg	missense_variant	Exon 8 of 12	5	NM_031232.4	ENSP00000246190.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000129 AC: 3 AN: 231772 Hom.: 0 AF XY: 0.00000781 AC XY: 1 AN XY: 128094

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: 0.0000564

Gnomad NFE exome AF: 0.0000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000757 AC: 11 AN: 1453216 Hom.: 0 Cov.: 33 AF XY: 0.00000692 AC XY: 5 AN XY: 722824

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: 0.0000206

Gnomad4 NFE exome AF: 0.00000901

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.680A>G (p.Q227R) alteration is located in exon 8 (coding exon 8) of the NECAB3 gene. This alteration results from a A to G substitution at nucleotide position 680, causing the glutamine (Q) at amino acid position 227 to be replaced by an arginine (R). 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	Uncertain	0.43
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.92	D;D;T;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.0	M;M;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.0	D;D;.;.;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D;D;.;.;D
Sift4G	Uncertain	0.0030	D;D;.;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.58
MutPred		0.61		Gain of MoRF binding (P = 0.0357);Gain of MoRF binding (P = 0.0357);.;Gain of MoRF binding (P = 0.0357);Gain of MoRF binding (P = 0.0357);
MVP		0.39
MPC		1.1
ClinPred		0.95	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.79

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: rs1255816144; hg19: chr20-32247502;