chr2-127062150-G-T

Variant names:

• chr2-127062150-G-T
• rs368730077
• NM_139343.3:c.822C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139343.3(BIN1):​c.822C>A​(p.His274Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H274Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BIN1 NM_139343.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.482
• 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09007418).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	NM_139343.3	MANE Select	c.822C>A	p.His274Gln	missense	Exon 10 of 19	NP_647593.1
	BIN1	NM_001320642.1		c.741C>A	p.His247Gln	missense	Exon 10 of 19	NP_001307571.1
	BIN1	NM_001320641.2		c.729C>A	p.His243Gln	missense	Exon 9 of 18	NP_001307570.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	ENST00000316724.10	TSL:1 MANE Select	c.822C>A	p.His274Gln	missense	Exon 10 of 19	ENSP00000316779.5
	BIN1	ENST00000357970.7	TSL:1	c.822C>A	p.His274Gln	missense	Exon 10 of 18	ENSP00000350654.3
	BIN1	ENST00000346226.7	TSL:1	c.729C>A	p.His243Gln	missense	Exon 9 of 16	ENSP00000315411.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458744 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725274

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.0000225 AC: 1 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110860

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.73
DANN	Benign	0.91
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		-0.48
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.058
Sift	Benign	0.056	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.38		Gain of helix (P = 0.0696)
MVP		0.60
MPC		0.26
ClinPred		0.33	T
GERP RS		-5.1
Varity_R		0.19
gMVP		0.51
Mutation Taster		=65/35	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: rs368730077; hg19: chr2-127819726;