chr2-127059149-G-A

Variant names:

• chr2-127059149-G-A
• rs746393271
• NM_139343.3:c.864C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_139343.3(BIN1):​c.864C>T​(p.Asn288Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000421 in 1,424,294 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: BIN1 NM_139343.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.116
• Publications: 0 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-127059149-G-A is Benign according to our data. Variant chr2-127059149-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 530870.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.116 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139343.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	NM_139343.3	MANE Select	c.864C>T	p.Asn288Asn	synonymous	Exon 11 of 19	NP_647593.1
	BIN1	NM_001320642.1		c.783C>T	p.Asn261Asn	synonymous	Exon 11 of 19	NP_001307571.1
	BIN1	NM_001320641.2		c.771C>T	p.Asn257Asn	synonymous	Exon 10 of 18	NP_001307570.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	ENST00000316724.10	TSL:1 MANE Select	c.864C>T	p.Asn288Asn	synonymous	Exon 11 of 19	ENSP00000316779.5
	BIN1	ENST00000357970.7	TSL:1	c.864C>T	p.Asn288Asn	synonymous	Exon 11 of 18	ENSP00000350654.3
	BIN1	ENST00000346226.7	TSL:1	c.771C>T	p.Asn257Asn	synonymous	Exon 10 of 16	ENSP00000315411.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183842 AF XY: 0.0000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000364

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000421 AC: 6 AN: 1424294 Hom.: 0 Cov.: 35 AF XY: 0.00000284 AC XY: 2 AN XY: 704986

African (AFR) AF: 0.00 AC: 0 AN: 32876

American (AMR) AF: 0.0000258 AC: 1 AN: 38826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25370

East Asian (EAS) AF: 0.0000526 AC: 2 AN: 37998

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1093526

Other (OTH) AF: 0.00 AC: 0 AN: 59016

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Myopathy, centronuclear, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.8
DANN	Benign	0.60
PhyloP100		-0.12
Mutation Taster		=100/0	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: rs746393271; hg19: chr2-127816725; COSMIC: COSV52121952; COSMIC: COSV52121952;