rs200580275

chr2-127051230-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_139343.3(BIN1):c.1385C>T(p.Ser462Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,610 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: BIN1 NM_139343.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.543

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0057593584).
• BP6: Variant 2-127051230-G-A is Benign according to our data. Variant chr2-127051230-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 461703.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BIN1	NM_139343.3	c.1385C>T	p.Ser462Leu	missense_variant	16/19	ENST00000316724.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BIN1	ENST00000316724.10	c.1385C>T	p.Ser462Leu	missense_variant	16/19	1	NM_139343.3

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000328 AC: 82 AN: 249770 Hom.: 0 AF XY: 0.000362 AC XY: 49 AN XY: 135384

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: 0.00336

Gnomad NFE exome AF: 0.0000710

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000122 AC: 179 AN: 1461466 Hom.: 1 Cov.: 33 AF XY: 0.000113 AC XY: 82 AN XY: 727052

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00286

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.000431 AC XY: 32 AN XY: 74328

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000239 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, centronuclear, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.060	N
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.0058	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	D;D;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	N;N;N;D;N;N;N;N;N
REVEL	Benign	0.047
Sift	Uncertain	0.027	D;T;T;T;T;D;T;D;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T
Polyphen		0.30	B;B;B;B;B;B;B;B;B
Vest4		0.27
MVP		0.54
MPC		0.23
ClinPred		0.032	T
GERP RS		2.3
Varity_R		0.064
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200580275; hg19: chr2-127808806;