4-40823714-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004307.2(APBB2):​c.1862C>T​(p.Ser621Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

APBB2
NM_004307.2 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.56
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.40504196).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
APBB2NM_004307.2 linkuse as main transcriptc.1862C>T p.Ser621Phe missense_variant 16/18 ENST00000508593.6 NP_004298.1 B4DJ88

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APBB2ENST00000508593.6 linkuse as main transcriptc.1862C>T p.Ser621Phe missense_variant 16/181 NM_004307.2 ENSP00000427211.1 Q92870-4

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000321
AC:
8
AN:
249432
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135348
show subpopulations
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:
0.0000466
Gnomad NFE exome
AF:
0.0000530
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000349
AC:
51
AN:
1461590
Hom.:
0
Cov.:
30
AF XY:
0.0000344
AC XY:
25
AN XY:
727126
show subpopulations
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:
0.000188
Gnomad4 NFE exome
AF:
0.0000369
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.000206
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000496
AC:
6
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 15, 2024The c.1862C>T (p.S621F) alteration is located in exon 16 (coding exon 12) of the APBB2 gene. This alteration results from a C to T substitution at nucleotide position 1862, causing the serine (S) at amino acid position 621 to be replaced by a phenylalanine (F). 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
0.19
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.18
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.30
T;.;.;.;.;T;.;T;T;T;T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;.;D;.;D;D;D;D
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.41
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M;.;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-1.9
N;D;N;N;D;N;D;N;D;D;D
REVEL
Benign
0.28
Sift
Uncertain
0.016
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.041
D;D;D;D;D;D;D;.;D;D;D
Polyphen
1.0
D;.;D;.;.;.;.;.;.;.;.
Vest4
0.58
MutPred
0.56
Loss of disorder (P = 0.0012);.;.;.;.;.;.;.;.;.;.;
MVP
0.63
MPC
1.3
ClinPred
0.45
T
GERP RS
5.8
Varity_R
0.13
gMVP
0.64

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs745627935; hg19: chr4-40825731; COSMIC: COSV99923570; COSMIC: COSV99923570; API