rs1801922908

Variant names:

• chr8-22623943-G-A
• rs1801922908
• NM_018688.6:c.587C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-22623943-G-A
• chr8-22623943-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018688.6(BIN3):​c.587C>T​(p.Pro196Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BIN3 NM_018688.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.83
• Publications: 0 publications found

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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018688.6. 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
	BIN3	NM_018688.6	MANE Select	c.587C>T	p.Pro196Leu	missense	Exon 8 of 9	NP_061158.1	Q9NQY0-1
	BIN3	NM_001363046.2		c.443C>T	p.Pro148Leu	missense	Exon 7 of 8	NP_001349975.1	H7BYV6
	BIN3	NR_156436.2		n.657C>T		non_coding_transcript_exon	Exon 8 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN3	ENST00000276416.11	TSL:1 MANE Select	c.587C>T	p.Pro196Leu	missense	Exon 8 of 9	ENSP00000276416.6	Q9NQY0-1
	BIN3	ENST00000853250.1		c.599C>T	p.Pro200Leu	missense	Exon 8 of 9	ENSP00000523309.1
	BIN3	ENST00000939253.1		c.524C>T	p.Pro175Leu	missense	Exon 8 of 9	ENSP00000609312.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459666 Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0 AN XY: 726018

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 85982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111406

Other (OTH) AF: 0.00 AC: 0 AN: 60282

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Uncertain	0.56
Sift	Benign	0.30	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.90	P
Vest4		0.93
MutPred		0.88		Loss of phosphorylation at Y193 (P = 0.1)
MVP		0.83
ClinPred		0.95	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.70
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1801922908; hg19: chr8-22481456;