rs114833236

Variant names:

• chr2-127059125-G-A
• rs114833236
• NM_139343.3:c.888C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_139343.3(BIN1):​c.888C>T​(p.Ser296Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00767 in 1,590,438 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (69 hom.)
• Consequence: BIN1 NM_139343.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.36
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-127059125-G-A is Benign according to our data. Variant chr2-127059125-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158021.
• BP7: Synonymous conserved (PhyloP=1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00394 (600/152262) while in subpopulation NFE AF = 0.00726 (494/68008). AF 95% confidence interval is 0.00673. There are 0 homozygotes in GnomAd4. There are 249 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 69 AR,AD,SD gene

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.888C>T	p.Ser296Ser	synonymous	Exon 11 of 19	NP_647593.1	O00499-1
	BIN1	NM_001320642.1		c.807C>T	p.Ser269Ser	synonymous	Exon 11 of 19	NP_001307571.1	O00499
	BIN1	NM_001320641.2		c.795C>T	p.Ser265Ser	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.888C>T	p.Ser296Ser	synonymous	Exon 11 of 19	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.888C>T	p.Ser296Ser	synonymous	Exon 11 of 18	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.795C>T	p.Ser265Ser	synonymous	Exon 10 of 16	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 600 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00726

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00367 AC: 760 AN: 207026 AF XY: 0.00365

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000235

Gnomad NFE exome AF: 0.00683

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00807 AC: 11604 AN: 1438176 Hom.: 69 Cov.: 35 AF XY: 0.00782 AC XY: 5574 AN XY: 713052

African (AFR) AF: 0.00102 AC: 34 AN: 33200

American (AMR) AF: 0.00105 AC: 43 AN: 41124

Ashkenazi Jewish (ASJ) AF: 0.00434 AC: 111 AN: 25562

East Asian (EAS) AF: 0.00 AC: 0 AN: 38766

South Asian (SAS) AF: 0.000998 AC: 82 AN: 82152

European-Finnish (FIN) AF: 0.000216 AC: 11 AN: 50818

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.00991 AC: 10909 AN: 1101308

Other (OTH) AF: 0.00694 AC: 413 AN: 59500

GnomAD4 genome AF: 0.00394 AC: 600 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00334 AC XY: 249 AN XY: 74450

African (AFR) AF: 0.00142 AC: 59 AN: 41552

American (AMR) AF: 0.000915 AC: 14 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00726 AC: 494 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00552 Hom.: 5

Bravo AF: 0.00391

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.6
DANN	Benign	0.61
PhyloP100		1.4
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: rs114833236; hg19: chr2-127816701; COSMIC: COSV52117520; COSMIC: COSV52117520;