rs1060743

Variant names:

• chr2-127068957-A-G
• rs1060743
• NM_139343.3:c.486T>C

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.486T>C​(p.Thr162Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,613,848 control chromosomes in the GnomAD database, including 79,706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7058 hom., cov: 34)
  • Exomes 𝑓: 0.31 (72648 hom.)
• Consequence: BIN1 NM_139343.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.58
• Publications: 36 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=-0.81).
• BP6: Variant 2-127068957-A-G is Benign according to our data. Variant chr2-127068957-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.432 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.486T>C	p.Thr162Thr	synonymous	Exon 6 of 19	NP_647593.1	O00499-1
	BIN1	NM_001320642.1		c.405T>C	p.Thr135Thr	synonymous	Exon 6 of 19	NP_001307571.1	O00499
	BIN1	NM_001320641.2		c.486T>C	p.Thr162Thr	synonymous	Exon 6 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.486T>C	p.Thr162Thr	synonymous	Exon 6 of 19	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.486T>C	p.Thr162Thr	synonymous	Exon 6 of 18	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.486T>C	p.Thr162Thr	synonymous	Exon 6 of 16	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45238 AN: 152000 Hom.: 7047 Cov.: 34

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.304

GnomAD2 exomes AF: 0.337 AC: 84816 AN: 251346 AF XY: 0.342

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.441

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.311 AC: 455011 AN: 1461728 Hom.: 72648 Cov.: 52 AF XY: 0.315 AC XY: 229265 AN XY: 727170

African (AFR) AF: 0.242 AC: 8112 AN: 33478

American (AMR) AF: 0.389 AC: 17404 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 7363 AN: 26130

East Asian (EAS) AF: 0.378 AC: 15024 AN: 39700

South Asian (SAS) AF: 0.436 AC: 37566 AN: 86250

European-Finnish (FIN) AF: 0.301 AC: 16066 AN: 53360

Middle Eastern (MID) AF: 0.307 AC: 1768 AN: 5768

European-Non Finnish (NFE) AF: 0.299 AC: 332833 AN: 1111932

Other (OTH) AF: 0.313 AC: 18875 AN: 60394

GnomAD4 genome AF: 0.298 AC: 45280 AN: 152120 Hom.: 7058 Cov.: 34 AF XY: 0.303 AC XY: 22513 AN XY: 74374

African (AFR) AF: 0.243 AC: 10085 AN: 41520

American (AMR) AF: 0.361 AC: 5520 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1032 AN: 3470

East Asian (EAS) AF: 0.431 AC: 2226 AN: 5168

South Asian (SAS) AF: 0.448 AC: 2160 AN: 4822

European-Finnish (FIN) AF: 0.292 AC: 3096 AN: 10596

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20162 AN: 67940

Other (OTH) AF: 0.300 AC: 633 AN: 2112

Alfa AF: 0.302 Hom.: 29372

Bravo AF: 0.299

Asia WGS AF: 0.445 AC: 1546 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.299

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Myopathy, centronuclear, 2 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.062
DANN	Benign	0.52
PhyloP100		-2.6
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: rs1060743; hg19: chr2-127826533; COSMIC: COSV52118719; COSMIC: COSV52118719;