rs61748155

Variant names:

• chr2-127052264-C-A
• rs61748155
• NM_139343.3:c.1362G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-127052264-C-A
• chr2-127052264-C-G
• chr2-127052264-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_139343.3(BIN1):​c.1362G>T​(p.Gly454Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,572,668 control chromosomes in the GnomAD database, including 494 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. G454G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (40 hom., cov: 34)
  • Exomes 𝑓: 0.023 (454 hom.)
• Consequence: BIN1 NM_139343.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.197
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-127052264-C-A is Benign according to our data. Variant chr2-127052264-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.197 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0504 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.1362G>T	p.Gly454Gly	synonymous	Exon 15 of 19	NP_647593.1	O00499-1
	BIN1	NM_001320642.1		c.1281G>T	p.Gly427Gly	synonymous	Exon 15 of 19	NP_001307571.1	O00499
	BIN1	NM_001320641.2		c.1269G>T	p.Gly423Gly	synonymous	Exon 14 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.1362G>T	p.Gly454Gly	synonymous	Exon 15 of 19	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.1233G>T	p.Gly411Gly	synonymous	Exon 14 of 18	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.1137G>T	p.Gly379Gly	synonymous	Exon 12 of 16	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2442 AN: 152234 Hom.: 40 Cov.: 34

Gnomad AFR AF: 0.00446

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0490

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0203 AC: 3632 AN: 178980 AF XY: 0.0229

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.00926

Gnomad ASJ exome AF: 0.00890

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.0226

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0229 AC: 32552 AN: 1420316 Hom.: 454 Cov.: 32 AF XY: 0.0241 AC XY: 16959 AN XY: 702538

African (AFR) AF: 0.00294 AC: 96 AN: 32692

American (AMR) AF: 0.00947 AC: 371 AN: 39182

Ashkenazi Jewish (ASJ) AF: 0.00815 AC: 207 AN: 25400

East Asian (EAS) AF: 0.0000798 AC: 3 AN: 37586

South Asian (SAS) AF: 0.0517 AC: 4176 AN: 80784

European-Finnish (FIN) AF: 0.0166 AC: 828 AN: 49814

Middle Eastern (MID) AF: 0.0285 AC: 159 AN: 5584

European-Non Finnish (NFE) AF: 0.0234 AC: 25476 AN: 1090576

Other (OTH) AF: 0.0211 AC: 1236 AN: 58698

GnomAD4 genome AF: 0.0160 AC: 2441 AN: 152352 Hom.: 40 Cov.: 34 AF XY: 0.0167 AC XY: 1243 AN XY: 74504

African (AFR) AF: 0.00445 AC: 185 AN: 41582

American (AMR) AF: 0.0150 AC: 230 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0493 AC: 238 AN: 4830

European-Finnish (FIN) AF: 0.0176 AC: 187 AN: 10626

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0222 AC: 1510 AN: 68030

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.0147 Hom.: 15

Bravo AF: 0.0141

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.6
DANN	Benign	0.72
PhyloP100		0.20
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: rs61748155; hg19: chr2-127809840;