rs112318500

Variant names:

• chr2-127050500-G-A
• rs112318500
• NM_139343.3:c.1595C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-127050500-G-A
• chr2-127050500-G-T
• chr2-127050500-G-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.1595C>T​(p.Thr532Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,614,214 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T532K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (182 hom., cov: 34)
  • Exomes 𝑓: 0.0028 (173 hom.)
• Consequence: BIN1 NM_139343.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.80
• Publications: 15 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 (MetaRNN=0.0031600595).
• BP6: Variant 2-127050500-G-A is Benign according to our data. Variant chr2-127050500-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0952 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.1595C>T	p.Thr532Met	missense	Exon 18 of 19	NP_647593.1	O00499-1
	BIN1	NM_001320642.1		c.1514C>T	p.Thr505Met	missense	Exon 18 of 19	NP_001307571.1	O00499
	BIN1	NM_001320641.2		c.1502C>T	p.Thr501Met	missense	Exon 17 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.1595C>T	p.Thr532Met	missense	Exon 18 of 19	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.1466C>T	p.Thr489Met	missense	Exon 17 of 18	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.1370C>T	p.Thr457Met	missense	Exon 15 of 16	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4329 AN: 152232 Hom.: 183 Cov.: 34

Gnomad AFR AF: 0.0979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.00752 AC: 1890 AN: 251352 AF XY: 0.00556

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00285 AC: 4160 AN: 1461864 Hom.: 173 Cov.: 32 AF XY: 0.00245 AC XY: 1780 AN XY: 727238

African (AFR) AF: 0.100 AC: 3360 AN: 33480

American (AMR) AF: 0.00532 AC: 238 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86256

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53404

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5766

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1112008

Other (OTH) AF: 0.00616 AC: 372 AN: 60396

GnomAD4 genome AF: 0.0284 AC: 4331 AN: 152350 Hom.: 182 Cov.: 34 AF XY: 0.0271 AC XY: 2021 AN XY: 74502

African (AFR) AF: 0.0977 AC: 4061 AN: 41574

American (AMR) AF: 0.0120 AC: 184 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68028

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

Alfa AF: 0.00994 Hom.: 196

Bravo AF: 0.0329

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0999 AC: 440

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00917 AC: 1113

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.14
Sift	Benign	0.032	D
Sift4G	Benign	0.092	T
Polyphen		0.86	P
Vest4		0.41
MVP		0.79
MPC		0.56
ClinPred		0.028	T
GERP RS		3.7
Varity_R		0.18
gMVP		0.32
Mutation Taster		=98/2	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: rs112318500; hg19: chr2-127808076;