rs201576067

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr20-33659970-C-G
• chr20-33659970-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_031232.4(NECAB3):​c.558G>C​(p.Arg186Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,564,466 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: NECAB3 NM_031232.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.522
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043815285).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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>C	p.Arg186Ser	missense	Exon 7 of 12	NP_112509.3
	NECAB3	NM_031231.4		c.558G>C	p.Arg186Ser	missense	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>C	p.Arg186Ser	missense	Exon 7 of 12	ENSP00000246190.6	Q96P71-1
	NECAB3	ENST00000375238.8	TSL:1	c.558G>C	p.Arg186Ser	missense	Exon 7 of 13	ENSP00000364386.4	Q96P71-2
	NECAB3	ENST00000883747.1		c.558G>C	p.Arg186Ser	missense	Exon 7 of 12	ENSP00000553806.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000149 AC: 25 AN: 168344 AF XY: 0.000153

Gnomad AFR exome AF: 0.000108

Gnomad AMR exome AF: 0.0000384

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.000220

GnomAD4 exome AF: 0.000177 AC: 250 AN: 1412322 Hom.: 2 Cov.: 33 AF XY: 0.000173 AC XY: 121 AN XY: 698662

African (AFR) AF: 0.0000305 AC: 1 AN: 32748

American (AMR) AF: 0.0000270 AC: 1 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: 0.0000123 AC: 1 AN: 81006

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

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.000223 AC: 243 AN: 1089470

Other (OTH) AF: 0.0000511 AC: 3 AN: 58722

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74316

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67986

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000250 AC: 2

ExAC AF: 0.000180 AC: 21

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.0
DANN	Benign	0.50
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.52
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.12
Sift	Benign	0.68	T
Sift4G	Benign	0.86	T
Polyphen		0.0070	B
Vest4		0.24
MutPred		0.28		Loss of MoRF binding (P = 0.0196)
MVP		0.28
MPC		0.36
ClinPred		0.027	T
GERP RS		3.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.13
gMVP		0.33
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;