rs146271483

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_014806.5(RUSC2):c.119C>A(p.Thr40Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,569,812 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

RUSC2
NM_014806.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 3.47

Publications

1 publications found

Variant links:

Genes affected

RUSC2 (HGNC:23625): (RUN and SH3 domain containing 2) This gene encodes a RUN and SH3 domain containing protein that interacts with Rab1b and Rab1-binding protein GM130. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Jun 2012]

RUSC2 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 61
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae), PanelApp Australia

RUSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0123458505).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000657 (100/152266) while in subpopulation NFE AF = 0.00128 (87/68002). AF 95% confidence interval is 0.00106. There are 1 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014806.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUSC2	NM_014806.5	MANE Select	c.119C>A	p.Thr40Lys	missense	Exon 2 of 12	NP_055621.2	Q8N2Y8
RUSC2	NM_001135999.2		c.119C>A	p.Thr40Lys	missense	Exon 2 of 12	NP_001129471.2	Q8N2Y8
RUSC2	NM_001330740.2		c.-620-8420C>A		intron	N/A	NP_001317669.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUSC2	ENST00000361226.8	TSL:2 MANE Select	c.119C>A	p.Thr40Lys	missense	Exon 2 of 12	ENSP00000355177.3	Q8N2Y8
RUSC2	ENST00000455600.1	TSL:1	c.119C>A	p.Thr40Lys	missense	Exon 2 of 12	ENSP00000393922.1	Q8N2Y8
RUSC2	ENST00000866950.1		c.119C>A	p.Thr40Lys	missense	Exon 2 of 12	ENSP00000537009.1

Frequencies

GnomAD3 genomes

AF:

0.000657

AC:

100

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00128

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000510

AC:

109

AN:

213872

AF XY:

0.000571

show subpopulations

Gnomad AFR exome

AF:

0.000190

Gnomad AMR exome

AF:

0.000139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000506

Gnomad NFE exome

AF:

0.000976

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00119

AC:

1684

AN:

1417546

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

841

AN XY:

701156

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

32368

American (AMR)

AF:

0.000207

AC:

AN:

38610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22820

East Asian (EAS)

AF:

0.00

AC:

AN:

39116

South Asian (SAS)

AF:

0.0000257

AC:

AN:

77774

European-Finnish (FIN)

AF:

0.000154

AC:

AN:

52016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5544

European-Non Finnish (NFE)

AF:

0.00146

AC:

1593

AN:

1090836

Other (OTH)

AF:

0.00113

AC:

AN:

58462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

179

269

358

448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000657

AC:

100

AN:

152266

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41550

American (AMR)

AF:

0.000261

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00128

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000730

Hom.:

Bravo

AF:

0.000688

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000545

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal recessive 61 (2)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.011

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.68

M_CAP

Benign

0.0028

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

PhyloP100

3.5

PrimateAI

Benign

0.35

PROVEAN

Benign

0.67

REVEL

Benign

0.073

Sift

Benign

0.72

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.13

MVP

0.21

MPC

0.23

ClinPred

0.0093

GERP RS

4.1

Varity_R

0.071

gMVP

0.14

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over