rs2132550904

Variant names:

• chr9-35546663-C-T
• rs2132550904
• NM_014806.5:c.142C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014806.5(RUSC2):​c.142C>T​(p.Pro48Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,419,310 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RUSC2 NM_014806.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.194
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034226328).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUSC2	NM_014806.5	MANE Select	c.142C>T	p.Pro48Ser	missense	Exon 2 of 12	NP_055621.2	Q8N2Y8
	RUSC2	NM_001135999.2		c.142C>T	p.Pro48Ser	missense	Exon 2 of 12	NP_001129471.2	Q8N2Y8
	RUSC2	NM_001330740.2		c.-620-8397C>T		intron	N/A	NP_001317669.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUSC2	ENST00000361226.8	TSL:2 MANE Select	c.142C>T	p.Pro48Ser	missense	Exon 2 of 12	ENSP00000355177.3	Q8N2Y8
	RUSC2	ENST00000455600.1	TSL:1	c.142C>T	p.Pro48Ser	missense	Exon 2 of 12	ENSP00000393922.1	Q8N2Y8
	RUSC2	ENST00000866950.1		c.142C>T	p.Pro48Ser	missense	Exon 2 of 12	ENSP00000537009.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1419310 Hom.: 0 Cov.: 29 AF XY: 0.00000285 AC XY: 2 AN XY: 701910

African (AFR) AF: 0.00 AC: 0 AN: 32480

American (AMR) AF: 0.00 AC: 0 AN: 39030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22884

East Asian (EAS) AF: 0.00 AC: 0 AN: 39246

South Asian (SAS) AF: 0.00 AC: 0 AN: 78184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1091414

Other (OTH) AF: 0.00 AC: 0 AN: 58492

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.4
DANN	Benign	0.85
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.19
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.090
Sift	Benign	0.16	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.057
MutPred		0.15		Gain of glycosylation at P48 (P = 0.0884)
MVP		0.26
MPC		0.17
ClinPred		0.15	T
GERP RS		0.74
Varity_R		0.027
gMVP		0.38
Mutation Taster		=90/10	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: rs2132550904; hg19: chr9-35546660;