2-127057493-T-C

Position:

• chr2-127057493-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139343.3(BIN1):​c.1111A>G​(p.Ser371Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BIN1 NM_139343.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

Genes affected

BIN1 (HGNC:1052): (bridging integrator 1) This gene encodes several isoforms of a nucleocytoplasmic adaptor protein, one of which was initially identified as a MYC-interacting protein with features of a tumor suppressor. Isoforms that are expressed in the central nervous system may be involved in synaptic vesicle endocytosis and may interact with dynamin, synaptojanin, endophilin, and clathrin. Isoforms that are expressed in muscle and ubiquitously expressed isoforms localize to the cytoplasm and nucleus and activate a caspase-independent apoptotic process. Studies in mouse suggest that this gene plays an important role in cardiac muscle development. Alternate splicing of the gene results in several transcript variants encoding different isoforms. Aberrant splice variants expressed in tumor cell lines have also been described. [provided by RefSeq, Mar 2016]

BIN1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18927473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BIN1	NM_139343.3	c.1111A>G	p.Ser371Gly	missense_variant	12/19	ENST00000316724.10	NP_647593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BIN1	ENST00000316724.10	c.1111A>G	p.Ser371Gly	missense_variant	12/19	1	NM_139343.3	ENSP00000316779.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395178 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 687676

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, centronuclear, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 371 of the BIN1 protein (p.Ser371Gly). 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: 461700). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	Benign	0.21
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;.;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	.;.;.;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0090	D;D;T;D
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.021	B;B;P;P
Vest4		0.32
MutPred		0.17		.;.;.;Loss of glycosylation at S371 (P = 0.0158);
MVP		0.64
MPC		0.81
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.39
gMVP		0.40

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

Other links and lift over

dbSNP: rs1553456782; hg19: chr2-127815069;