rs121909273

Positions:

• chr2-127076686-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_139343.3(BIN1):​c.105G>T​(p.Lys35Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BIN1 NM_139343.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.24

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a coiled_coil_region (size 27) in uniprot entity BIN1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_139343.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 2-127076686-C-A is Pathogenic according to our data. Variant chr2-127076686-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 8297.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-127076686-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BIN1	NM_139343.3	c.105G>T	p.Lys35Asn	missense_variant	2/19	ENST00000316724.10	NP_647593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BIN1	ENST00000316724.10	c.105G>T	p.Lys35Asn	missense_variant	2/19	1	NM_139343.3	ENSP00000316779

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Myopathy, centronuclear, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;.;.;.;.;.;.;.;.;D;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.86	P;D;P;P;P;D;P;D;P;P;D
Vest4		0.65
MutPred		0.87		Loss of ubiquitination at K35 (P = 0.0127);Loss of ubiquitination at K35 (P = 0.0127);Loss of ubiquitination at K35 (P = 0.0127);Loss of ubiquitination at K35 (P = 0.0127);Loss of ubiquitination at K35 (P = 0.0127);Loss of ubiquitination at K35 (P = 0.0127);Loss of ubiquitination at K35 (P = 0.0127);Loss of ubiquitination at K35 (P = 0.0127);Loss of ubiquitination at K35 (P = 0.0127);Loss of ubiquitination at K35 (P = 0.0127);Loss of ubiquitination at K35 (P = 0.0127);
MVP		0.85
MPC		2.3
ClinPred		0.99	D
GERP RS		2.1
Varity_R		0.86
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909273; hg19: chr2-127834262; COSMIC: COSV99387455;