chr2-127106914-C-T

Variant names:

• chr2-127106914-C-T
• rs35535012
• NM_139343.3:c.30G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_139343.3(BIN1):​c.30G>A​(p.Thr10Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,612,798 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0018 (12 hom.)
• Consequence: BIN1 NM_139343.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: -0.408
• Publications: 3 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

LOC105373605 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 2-127106914-C-T is Benign according to our data. Variant chr2-127106914-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158014.
• BP7: Synonymous conserved (PhyloP=-0.408 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000775 (118/152302) while in subpopulation SAS AF = 0.00373 (18/4826). AF 95% confidence interval is 0.00241. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR,AD,SD gene

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.30G>A	p.Thr10Thr	synonymous	Exon 1 of 19	NP_647593.1	O00499-1
	BIN1	NM_001320641.2		c.30G>A	p.Thr10Thr	synonymous	Exon 1 of 18	NP_001307570.1
	BIN1	NM_139344.3		c.30G>A	p.Thr10Thr	synonymous	Exon 1 of 18	NP_647594.1	O00499-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	ENST00000316724.10	TSL:1 MANE Select	c.30G>A	p.Thr10Thr	synonymous	Exon 1 of 19	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.30G>A	p.Thr10Thr	synonymous	Exon 1 of 18	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.30G>A	p.Thr10Thr	synonymous	Exon 1 of 16	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152186 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00108 AC: 267 AN: 247062 AF XY: 0.00134

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.00176 AC: 2567 AN: 1460496 Hom.: 12 Cov.: 31 AF XY: 0.00179 AC XY: 1301 AN XY: 726592

African (AFR) AF: 0.000150 AC: 5 AN: 33418

American (AMR) AF: 0.000291 AC: 13 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00344 AC: 296 AN: 86152

European-Finnish (FIN) AF: 0.000190 AC: 10 AN: 52732

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00192 AC: 2137 AN: 1111630

Other (OTH) AF: 0.00167 AC: 101 AN: 60344

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152302 Hom.: 0 Cov.: 34 AF XY: 0.000900 AC XY: 67 AN XY: 74462

African (AFR) AF: 0.000240 AC: 10 AN: 41588

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00123 AC: 84 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.000676

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Uncertain	0.98
PhyloP100		-0.41
PromoterAI		-0.046	Neutral
Mutation Taster		=100/0	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: rs35535012; hg19: chr2-127864490;