rs368983991

Variant names:

• chr2-127048600-C-T
• rs368983991
• NM_139343.3:c.1708G>A

Variant summary

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

The NM_139343.3(BIN1):​c.1708G>A​(p.Asp570Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D570E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BIN1 NM_139343.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1708G>A	p.Asp570Asn	missense	Exon 19 of 19	NP_647593.1	O00499-1
	BIN1	NM_001320642.1		c.1627G>A	p.Asp543Asn	missense	Exon 19 of 19	NP_001307571.1	O00499
	BIN1	NM_001320641.2		c.1615G>A	p.Asp539Asn	missense	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.1708G>A	p.Asp570Asn	missense	Exon 19 of 19	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.1579G>A	p.Asp527Asn	missense	Exon 18 of 18	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.1483G>A	p.Asp495Asn	missense	Exon 16 of 16	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461206 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726906

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5388

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

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
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.33
Sift	Benign	0.12	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.60
MVP		0.90
MPC		0.91
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.65
gMVP		0.73
Mutation Taster		=45/55	disease causing

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: rs368983991; hg19: chr2-127806176; COSMIC: COSV52119395; COSMIC: COSV52119395;