rs2276579

Variant names:

• chr2-127059056-G-A
• rs2276579
• NM_139343.3:c.957C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-127059056-G-A
• chr2-127059056-G-C
• chr2-127059056-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_139343.3(BIN1):​c.957C>T​(p.Ala319Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,576,122 control chromosomes in the GnomAD database, including 28,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A319A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (2027 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26041 hom.)
• Consequence: BIN1 NM_139343.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.500
• Publications: 12 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-127059056-G-A is Benign according to our data. Variant chr2-127059056-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

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.957C>T	p.Ala319Ala	synonymous	Exon 11 of 19	NP_647593.1	O00499-1
	BIN1	NM_001320642.1		c.876C>T	p.Ala292Ala	synonymous	Exon 11 of 19	NP_001307571.1	O00499
	BIN1	NM_001320641.2		c.864C>T	p.Ala288Ala	synonymous	Exon 10 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.957C>T	p.Ala319Ala	synonymous	Exon 11 of 19	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.957C>T	p.Ala319Ala	synonymous	Exon 11 of 18	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.864C>T	p.Ala288Ala	synonymous	Exon 10 of 16	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21798 AN: 151992 Hom.: 2018 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.0482

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.162 AC: 30419 AN: 188192 AF XY: 0.163

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.0597

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.186 AC: 264790 AN: 1424012 Hom.: 26041 Cov.: 38 AF XY: 0.185 AC XY: 130316 AN XY: 704654

African (AFR) AF: 0.0306 AC: 1008 AN: 32890

American (AMR) AF: 0.166 AC: 6443 AN: 38724

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 4898 AN: 25412

East Asian (EAS) AF: 0.0385 AC: 1465 AN: 38100

South Asian (SAS) AF: 0.115 AC: 9359 AN: 81158

European-Finnish (FIN) AF: 0.161 AC: 8051 AN: 49884

Middle Eastern (MID) AF: 0.185 AC: 1054 AN: 5712

European-Non Finnish (NFE) AF: 0.203 AC: 222108 AN: 1093140

Other (OTH) AF: 0.176 AC: 10404 AN: 58992

GnomAD4 genome AF: 0.143 AC: 21822 AN: 152110 Hom.: 2027 Cov.: 32 AF XY: 0.141 AC XY: 10502 AN XY: 74352

African (AFR) AF: 0.0374 AC: 1552 AN: 41520

American (AMR) AF: 0.191 AC: 2922 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 716 AN: 3470

East Asian (EAS) AF: 0.0483 AC: 248 AN: 5134

South Asian (SAS) AF: 0.108 AC: 522 AN: 4816

European-Finnish (FIN) AF: 0.144 AC: 1526 AN: 10608

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13655 AN: 67954

Other (OTH) AF: 0.176 AC: 371 AN: 2110

Alfa AF: 0.147 Hom.: 759

Bravo AF: 0.143

Asia WGS AF: 0.0940 AC: 326 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Myopathy, centronuclear, 2 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.5
DANN	Benign	0.48
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

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: rs2276579; hg19: chr2-127816632; COSMIC: COSV52118503; COSMIC: COSV52118503;