2-127050540-C-G

Variant names:

• chr2-127050540-C-G
• rs12466912
• NM_139343.3:c.1573-18G>C

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.1573-18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0384 in 1,613,712 control chromosomes in the GnomAD database, including 2,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (344 hom., cov: 34)
  • Exomes 𝑓: 0.037 (2479 hom.)
• Consequence: BIN1 NM_139343.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.32
• Publications: 4 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=-1.02).
• BP6: Variant 2-127050540-C-G is Benign according to our data. Variant chr2-127050540-C-G is described in ClinVar as Benign. ClinVar VariationId is 262474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 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.1573-18G>C		intron	N/A	NP_647593.1	O00499-1
	BIN1	NM_001320642.1		c.1492-18G>C		intron	N/A	NP_001307571.1	O00499
	BIN1	NM_001320641.2		c.1480-18G>C		intron	N/A	NP_001307570.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	ENST00000316724.10	TSL:1 MANE Select	c.1573-18G>C		intron	N/A	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.1444-18G>C		intron	N/A	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.1348-18G>C		intron	N/A	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7562 AN: 152226 Hom.: 343 Cov.: 34

Gnomad AFR AF: 0.0414

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0907

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0459

GnomAD2 exomes AF: 0.0754 AC: 18920 AN: 250800 AF XY: 0.0725

Gnomad AFR exome AF: 0.0402

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.144

Gnomad FIN exome AF: 0.0883

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0516

GnomAD4 exome AF: 0.0373 AC: 54474 AN: 1461368 Hom.: 2479 Cov.: 32 AF XY: 0.0391 AC XY: 28406 AN XY: 727046

African (AFR) AF: 0.0396 AC: 1325 AN: 33472

American (AMR) AF: 0.186 AC: 8290 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0388 AC: 1013 AN: 26134

East Asian (EAS) AF: 0.140 AC: 5542 AN: 39688

South Asian (SAS) AF: 0.118 AC: 10147 AN: 86226

European-Finnish (FIN) AF: 0.0834 AC: 4450 AN: 53358

Middle Eastern (MID) AF: 0.0400 AC: 231 AN: 5768

European-Non Finnish (NFE) AF: 0.0189 AC: 20988 AN: 1111678

Other (OTH) AF: 0.0412 AC: 2488 AN: 60384

GnomAD4 genome AF: 0.0497 AC: 7570 AN: 152344 Hom.: 344 Cov.: 34 AF XY: 0.0563 AC XY: 4195 AN XY: 74494

African (AFR) AF: 0.0415 AC: 1727 AN: 41578

American (AMR) AF: 0.112 AC: 1711 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3466

East Asian (EAS) AF: 0.157 AC: 814 AN: 5184

South Asian (SAS) AF: 0.128 AC: 620 AN: 4828

European-Finnish (FIN) AF: 0.0907 AC: 963 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0222 AC: 1508 AN: 68036

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0179 Hom.: 15

Bravo AF: 0.0514

Asia WGS AF: 0.147 AC: 511 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.17
DANN	Benign	0.38
PhyloP100		-1.3
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: rs12466912; hg19: chr2-127808116; COSMIC: COSV52118920;