chr20-33659970-C-T

Variant names:

• chr20-33659970-C-T
• rs201576067
• NM_031232.4:c.558G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_031232.4(NECAB3):​c.558G>A​(p.Arg186Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,412,322 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NECAB3 NM_031232.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.522
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP7: Synonymous conserved (PhyloP=0.522 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031232.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NECAB3	NM_031232.4	MANE Select	c.558G>A	p.Arg186Arg	synonymous	Exon 7 of 12	NP_112509.3
	NECAB3	NM_031231.4		c.558G>A	p.Arg186Arg	synonymous	Exon 7 of 13	NP_112508.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NECAB3	ENST00000246190.11	TSL:5 MANE Select	c.558G>A	p.Arg186Arg	synonymous	Exon 7 of 12	ENSP00000246190.6	Q96P71-1
	NECAB3	ENST00000375238.8	TSL:1	c.558G>A	p.Arg186Arg	synonymous	Exon 7 of 13	ENSP00000364386.4	Q96P71-2
	NECAB3	ENST00000883747.1		c.558G>A	p.Arg186Arg	synonymous	Exon 7 of 12	ENSP00000553806.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1412322 Hom.: 0 Cov.: 33 AF XY: 0.00000429 AC XY: 3 AN XY: 698662

African (AFR) AF: 0.00 AC: 0 AN: 32748

American (AMR) AF: 0.00 AC: 0 AN: 37080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25288

East Asian (EAS) AF: 0.00 AC: 0 AN: 37588

South Asian (SAS) AF: 0.00 AC: 0 AN: 81006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1089470

Other (OTH) AF: 0.00 AC: 0 AN: 58722

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.6
DANN	Benign	0.64
PhyloP100		0.52
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201576067; hg19: chr20-32247776;