2-127059119-C-T

Variant names:

• chr2-127059119-C-T
• rs2228955
• NM_139343.3:c.894G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139343.3(BIN1):​c.894G>A​(p.Ser298Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0362 in 1,591,624 control chromosomes in the GnomAD database, including 2,541 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. S298S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.042 (300 hom., cov: 32)
  • Exomes 𝑓: 0.036 (2241 hom.)
• Consequence: BIN1 NM_139343.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.21
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-127059119-C-T is Benign according to our data. Variant chr2-127059119-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.147 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.894G>A	p.Ser298Ser	synonymous	Exon 11 of 19	NP_647593.1	O00499-1
	BIN1	NM_001320642.1		c.813G>A	p.Ser271Ser	synonymous	Exon 11 of 19	NP_001307571.1	O00499
	BIN1	NM_001320641.2		c.801G>A	p.Ser267Ser	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.894G>A	p.Ser298Ser	synonymous	Exon 11 of 19	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.894G>A	p.Ser298Ser	synonymous	Exon 11 of 18	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.801G>A	p.Ser267Ser	synonymous	Exon 10 of 16	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 6389 AN: 151686 Hom.: 301 Cov.: 32

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0900

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0412

GnomAD2 exomes AF: 0.0732 AC: 15335 AN: 209514 AF XY: 0.0703

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.0385

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.0853

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0468

GnomAD4 exome AF: 0.0355 AC: 51154 AN: 1439820 Hom.: 2241 Cov.: 35 AF XY: 0.0374 AC XY: 26691 AN XY: 713978

African (AFR) AF: 0.0131 AC: 435 AN: 33236

American (AMR) AF: 0.179 AC: 7363 AN: 41216

Ashkenazi Jewish (ASJ) AF: 0.0382 AC: 978 AN: 25600

East Asian (EAS) AF: 0.138 AC: 5363 AN: 38834

South Asian (SAS) AF: 0.116 AC: 9552 AN: 82336

European-Finnish (FIN) AF: 0.0822 AC: 4180 AN: 50846

Middle Eastern (MID) AF: 0.0367 AC: 211 AN: 5750

European-Non Finnish (NFE) AF: 0.0188 AC: 20760 AN: 1102402

Other (OTH) AF: 0.0388 AC: 2312 AN: 59600

GnomAD4 genome AF: 0.0421 AC: 6389 AN: 151804 Hom.: 300 Cov.: 32 AF XY: 0.0492 AC XY: 3646 AN XY: 74164

African (AFR) AF: 0.0156 AC: 647 AN: 41368

American (AMR) AF: 0.109 AC: 1668 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 124 AN: 3470

East Asian (EAS) AF: 0.156 AC: 798 AN: 5124

South Asian (SAS) AF: 0.128 AC: 612 AN: 4786

European-Finnish (FIN) AF: 0.0900 AC: 947 AN: 10524

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0221 AC: 1503 AN: 67942

Other (OTH) AF: 0.0389 AC: 82 AN: 2110

Alfa AF: 0.0261 Hom.: 194

Bravo AF: 0.0429

Asia WGS AF: 0.145 AC: 504 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	-0.78
CADD	Benign	0.85
DANN	Benign	0.75
PhyloP100		-4.2
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: rs2228955; hg19: chr2-127816695; COSMIC: COSV52120699; COSMIC: COSV52120699;