chr4-40823649-C-T

Variant names:

• chr4-40823649-C-T
• rs756658820
• NM_004307.2:c.1927G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004307.2(APBB2):​c.1927G>A​(p.Glu643Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000647 in 1,608,286 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (1 hom.)
• Consequence: APBB2 NM_004307.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00
• Publications: 0 publications found

Genes affected

APBB2 (HGNC:582): (amyloid beta precursor protein binding family B member 2) The protein encoded by this gene interacts with the cytoplasmic domains of amyloid beta (A4) precursor protein and amyloid beta (A4) precursor-like protein 2. This protein contains two phosphotyrosine binding (PTB) domains, which are thought to function in signal transduction. Polymorphisms in this gene have been associated with Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ENSG00000250906 (HGNC:58763):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09228912).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004307.2. 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
	APBB2	NM_004307.2	MANE Select	c.1927G>A	p.Glu643Lys	missense	Exon 16 of 18	NP_004298.1	Q92870-4
	APBB2	NM_001166050.2		c.1924G>A	p.Glu642Lys	missense	Exon 16 of 18	NP_001159522.1	Q92870-1
	APBB2	NM_001330656.2		c.1861G>A	p.Glu621Lys	missense	Exon 15 of 17	NP_001317585.1	G5E9Y1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APBB2	ENST00000508593.6	TSL:1 MANE Select	c.1927G>A	p.Glu643Lys	missense	Exon 16 of 18	ENSP00000427211.1	Q92870-4
	APBB2	ENST00000513140.5	TSL:1	c.1858G>A	p.Glu620Lys	missense	Exon 15 of 17	ENSP00000426018.1	Q92870-2
	APBB2	ENST00000894650.1		c.1927G>A	p.Glu643Lys	missense	Exon 15 of 17	ENSP00000564709.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000128 AC: 32 AN: 249334 AF XY: 0.000118

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000680 AC: 99 AN: 1456066 Hom.: 1 Cov.: 28 AF XY: 0.0000773 AC XY: 56 AN XY: 724904

African (AFR) AF: 0.0000300 AC: 1 AN: 33366

American (AMR) AF: 0.000559 AC: 25 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.0000425 AC: 47 AN: 1106942

Other (OTH) AF: 0.000282 AC: 17 AN: 60250

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74360

African (AFR) AF: 0.0000482 AC: 2 AN: 41452

American (AMR) AF: 0.000196 AC: 3 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000114 Hom.: 1

Bravo AF: 0.0000718

ExAC AF: 0.0000992 AC: 12

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	0.094
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.082
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.088
Sift	Benign	0.10	T
Sift4G	Benign	0.73	T
Polyphen		0.012	B
Vest4		0.48
MutPred		0.63		Gain of ubiquitination at E642 (P = 0.0131)
MVP		0.42
MPC		0.50
ClinPred		0.016	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.45
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs756658820; hg19: chr4-40825666;