rs371258305

Variant names:

• chr2-127059107-G-A
• rs371258305
• NM_139343.3:c.906C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_139343.3(BIN1):​c.906C>T​(p.Gly302Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,594,404 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: BIN1 NM_139343.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.337
• Publications: 0 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):

• myopathy, centronuclear, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• centronuclear myopathy

  Inheritance: SD, AR, AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-127059107-G-A is Benign according to our data. Variant chr2-127059107-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262480.
• BP7: Synonymous conserved (PhyloP=0.337 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000296 (45/152220) while in subpopulation NFE AF = 0.000544 (37/67994). AF 95% confidence interval is 0.000405. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.906C>T	p.Gly302Gly	synonymous	Exon 11 of 19	NP_647593.1
	BIN1	NM_001320642.1		c.825C>T	p.Gly275Gly	synonymous	Exon 11 of 19	NP_001307571.1
	BIN1	NM_001320641.2		c.813C>T	p.Gly271Gly	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.906C>T	p.Gly302Gly	synonymous	Exon 11 of 19	ENSP00000316779.5
	BIN1	ENST00000357970.7	TSL:1	c.906C>T	p.Gly302Gly	synonymous	Exon 11 of 18	ENSP00000350654.3
	BIN1	ENST00000346226.7	TSL:1	c.813C>T	p.Gly271Gly	synonymous	Exon 10 of 16	ENSP00000315411.3

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000211 AC: 45 AN: 213738 AF XY: 0.000208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000465

Gnomad NFE exome AF: 0.000357

Gnomad OTH exome AF: 0.000556

GnomAD4 exome AF: 0.000329 AC: 475 AN: 1442184 Hom.: 0 Cov.: 35 AF XY: 0.000327 AC XY: 234 AN XY: 715396

African (AFR) AF: 0.0000601 AC: 2 AN: 33254

American (AMR) AF: 0.00 AC: 0 AN: 41820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25624

East Asian (EAS) AF: 0.00 AC: 0 AN: 39034

South Asian (SAS) AF: 0.00 AC: 0 AN: 82608

European-Finnish (FIN) AF: 0.000687 AC: 35 AN: 50920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000384 AC: 424 AN: 1103468

Other (OTH) AF: 0.000234 AC: 14 AN: 59706

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74430

African (AFR) AF: 0.0000482 AC: 2 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 67994

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000357 Hom.: 0

Bravo AF: 0.000242

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.4
DANN	Benign	0.81
PhyloP100		0.34
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: rs371258305; hg19: chr2-127816683;