2-127048113-C-T

Variant names:

• chr2-127048113-C-T
• rs886054829
• NM_139343.3:c.*413G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_139343.3(BIN1):​c.*413G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 278,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: BIN1 NM_139343.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05
• 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):

• centronuclear myopathy

  Inheritance: AD, AR, SD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• myopathy, centronuclear, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	NM_139343.3	MANE Select	c.*413G>A		3_prime_UTR	Exon 19 of 19	NP_647593.1	O00499-1
	BIN1	NM_001320642.1		c.*413G>A		3_prime_UTR	Exon 19 of 19	NP_001307571.1	O00499
	BIN1	NM_001320641.2		c.*413G>A		3_prime_UTR	Exon 18 of 18	NP_001307570.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	ENST00000316724.10	TSL:1 MANE Select	c.*413G>A		3_prime_UTR	Exon 19 of 19	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.*413G>A		3_prime_UTR	Exon 18 of 18	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.*413G>A		3_prime_UTR	Exon 16 of 16	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152206 Hom.: 1 Cov.: 33

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000477 AC: 6 AN: 125882 Hom.: 0 Cov.: 0 AF XY: 0.0000605 AC XY: 4 AN XY: 66126

African (AFR) AF: 0.00 AC: 0 AN: 4052

American (AMR) AF: 0.00 AC: 0 AN: 4976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3236

East Asian (EAS) AF: 0.00 AC: 0 AN: 5630

South Asian (SAS) AF: 0.00 AC: 0 AN: 19094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 474

European-Non Finnish (NFE) AF: 0.0000799 AC: 6 AN: 75064

Other (OTH) AF: 0.00 AC: 0 AN: 6512

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152206 Hom.: 1 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-0.46
CADD	Benign	16
DANN	Benign	0.87
PhyloP100		2.1
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: rs886054829; hg19: chr2-127805689;