8-22630533-T-C

Variant names:

• chr8-22630533-T-C
• rs368195300
• NM_018688.6:c.206A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018688.6(BIN3):​c.206A>G​(p.Asn69Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: BIN3 NM_018688.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53

Genes affected

BIN3 (HGNC:1054): (bridging integrator 3) The product of this gene is a member of the BAR domain protein family. The encoded protein is comprised solely of a BAR domain which is predicted to form coiled-coil structures and proposed to mediate dimerization, sense and induce membrane curvature, and bind small GTPases. BAR domain proteins have been implicated in endocytosis, intracellular transport, and a diverse set of other processes. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058100283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BIN3	NM_018688.6	c.206A>G	p.Asn69Ser	missense_variant	Exon 5 of 9	ENST00000276416.11	NP_061158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BIN3	ENST00000276416.11	c.206A>G	p.Asn69Ser	missense_variant	Exon 5 of 9	1	NM_018688.6	ENSP00000276416.6

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000277 AC: 69 AN: 249246 AF XY: 0.000259

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00139

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1461696 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 88 AN XY: 727130

Gnomad4 AFR exome AF: 0.000119 AC: 4 AN: 33480

Gnomad4 AMR exome AF: 0.000358 AC: 16 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.000982 AC: 39 AN: 39700

Gnomad4 SAS exome AF: 0.000313 AC: 27 AN: 86258

Gnomad4 FIN exome AF: 0.0000936 AC: 5 AN: 53398

Gnomad4 NFE exome AF: 0.0000693 AC: 77 AN: 1111860

Gnomad4 Remaining exome AF: 0.000133 AC: 8 AN: 60372

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74460

Gnomad4 AFR AF: 0.0000481 AC: 0.0000481417 AN: 0.0000481417

Gnomad4 AMR AF: 0.000131 AC: 0.000130668 AN: 0.000130668

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000579 AC: 0.000579374 AN: 0.000579374

Gnomad4 SAS AF: 0.000208 AC: 0.000207555 AN: 0.000207555

Gnomad4 FIN AF: 0.000188 AC: 0.000188218 AN: 0.000188218

Gnomad4 NFE AF: 0.000132 AC: 0.000132318 AN: 0.000132318

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000998 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000199 AC: 24

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.206A>G (p.N69S) alteration is located in exon 5 (coding exon 5) of the BIN3 gene. This alteration results from a A to G substitution at nucleotide position 206, causing the asparagine (N) at amino acid position 69 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;T;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.058	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N;N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.20	T;T;T;T;.
Sift4G	Benign	0.10	T;T;T;D;.
Polyphen		0.45	B;.;.;.;.
Vest4		0.81
MutPred		0.51		Gain of phosphorylation at S68 (P = 0.1065);.;.;Gain of phosphorylation at S68 (P = 0.1065);Gain of phosphorylation at S68 (P = 0.1065);
MVP		0.52
ClinPred		0.11	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.52
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs368195300; hg19: chr8-22488046;