2-127048534-C-T

Variant names:

• chr2-127048534-C-T
• rs199908147
• NM_139343.3:c.1774G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139343.3(BIN1):​c.1774G>A​(p.Val592Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V592F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BIN1 NM_139343.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.70
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• myopathy, centronuclear, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• centronuclear myopathy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant centronuclear myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17206934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BIN1	NM_139343.3	c.1774G>A	p.Val592Ile	missense_variant	Exon 19 of 19	ENST00000316724.10	NP_647593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BIN1	ENST00000316724.10	c.1774G>A	p.Val592Ile	missense_variant	Exon 19 of 19	1	NM_139343.3	ENSP00000316779.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.093	.;.;.;.;.;.;.;.;.;T;.
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.0020
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.39	.;.;.;.;.;.;.;.;.;N;.
PhyloP100		2.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.050	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.62	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.28	B;B;P;B;P;P;P;B;D;P;P
Vest4		0.36
MutPred		0.49		.;.;.;.;.;.;.;.;.;Gain of catalytic residue at V592 (P = 0.0184);.;
MVP		0.65
MPC		0.34
ClinPred		0.46	T
GERP RS		4.0
Varity_R		0.031
gMVP		0.11
Mutation Taster		=88/12	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: rs199908147; hg19: chr2-127806110;