rs11554586

Variant names:

• chr2-127106970-G-A
• rs11554586
• NM_139343.3:c.-27C>T

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.-27C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,600,126 control chromosomes in the GnomAD database, including 22,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1690 hom., cov: 34)
  • Exomes 𝑓: 0.17 (21161 hom.)
• Consequence: BIN1 NM_139343.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.08
• Publications: 13 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• centronuclear myopathy

  Inheritance: SD Classification: DEFINITIVE 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

LOC105373605 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-127106970-G-A is Benign according to our data. Variant chr2-127106970-G-A is described in ClinVar as Benign. ClinVar VariationId is 262469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.179 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.-27C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	NP_647593.1
	BIN1	NM_139343.3	MANE Select	c.-27C>T		5_prime_UTR	Exon 1 of 19	NP_647593.1
	BIN1	NM_001320641.2		c.-27C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 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.-27C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	ENSP00000316779.5
	BIN1	ENST00000357970.7	TSL:1	c.-27C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000350654.3
	BIN1	ENST00000346226.7	TSL:1	c.-27C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000315411.3

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19852 AN: 152072 Hom.: 1684 Cov.: 34

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.0996

Gnomad SAS AF: 0.0631

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.141

GnomAD2 exomes AF: 0.152 AC: 34751 AN: 228148 AF XY: 0.152

Gnomad AFR exome AF: 0.0334

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.114

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.166 AC: 240804 AN: 1447940 Hom.: 21161 Cov.: 32 AF XY: 0.164 AC XY: 118321 AN XY: 720098

African (AFR) AF: 0.0270 AC: 867 AN: 32094

American (AMR) AF: 0.140 AC: 6146 AN: 43926

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4925 AN: 25858

East Asian (EAS) AF: 0.0861 AC: 3290 AN: 38230

South Asian (SAS) AF: 0.0707 AC: 5986 AN: 84628

European-Finnish (FIN) AF: 0.185 AC: 9303 AN: 50304

Middle Eastern (MID) AF: 0.153 AC: 879 AN: 5734

European-Non Finnish (NFE) AF: 0.180 AC: 199855 AN: 1107318

Other (OTH) AF: 0.160 AC: 9553 AN: 59848

GnomAD4 genome AF: 0.131 AC: 19869 AN: 152186 Hom.: 1690 Cov.: 34 AF XY: 0.129 AC XY: 9578 AN XY: 74394

African (AFR) AF: 0.0317 AC: 1319 AN: 41566

American (AMR) AF: 0.145 AC: 2211 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 700 AN: 3468

East Asian (EAS) AF: 0.0997 AC: 513 AN: 5148

South Asian (SAS) AF: 0.0646 AC: 312 AN: 4830

European-Finnish (FIN) AF: 0.177 AC: 1876 AN: 10598

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12353 AN: 67956

Other (OTH) AF: 0.139 AC: 295 AN: 2116

Alfa AF: 0.167 Hom.: 422

Bravo AF: 0.126

Asia WGS AF: 0.0910 AC: 316 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	17
DANN	Benign	0.97
PhyloP100		1.1
PromoterAI		0.077	Neutral
Mutation Taster		=300/0	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: rs11554586; hg19: chr2-127864546; COSMIC: COSV52119136;