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GeneBe

2-127048557-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2_SupportingPP3_Strong

The NM_139343.3(BIN1):c.1751T>C(p.Phe584Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000663 in 150758 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F584F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

BIN1
NM_139343.3 missense

Scores

12
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.28

Links

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
?
Very rare variant; Number of alleles below threshold, gnomad allele frequency = 0.00000663 (1/150758) while in subpopulation NFE AF= 0.0000148 (1/67536). AF 95% confidence interval is 0. There are 0 homozygotes in gnomad. There are 0 alleles in male gnomad subpopulation. Median coverage is 33. This position pass quality control queck.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BIN1NM_139343.3 linkuse as main transcriptc.1751T>C p.Phe584Ser missense_variant 19/19 ENST00000316724.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BIN1ENST00000316724.10 linkuse as main transcriptc.1751T>C p.Phe584Ser missense_variant 19/191 NM_139343.3 O00499-1

Frequencies

GnomAD3 genomes
AF:
0.00000663
AC:
1
AN:
150758
Hom.:
0
Cov.:
33
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000148
Gnomad OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

Myopathy, centronuclear, 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 22, 2022This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 584 of the BIN1 protein (p.Phe584Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BIN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1017301). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
Cadd
Pathogenic
27
Dann
Uncertain
1.0
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.18
D
MutationTaster
Benign
0.94
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-5.7
D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.73
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D;D;D;D;D;D
Vest4
0.98
MutPred
0.86
.;.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0084);.;
MVP
0.88
MPC
1.3
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.99
gMVP
0.95

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: rs1466748456; hg19: chr2-127806133; API