rs1164305616

Variant names:

• chr9-35546619-C-T
• rs1164305616
• NM_014806.5:c.98C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014806.5(RUSC2):​c.98C>T​(p.Ala33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,407,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 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: 0.000017 (0 hom.)
• Consequence: RUSC2 NM_014806.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.98C>T	p.Ala33Val	missense	Exon 2 of 12	NP_055621.2	Q8N2Y8
	RUSC2	NM_001135999.2		c.98C>T	p.Ala33Val	missense	Exon 2 of 12	NP_001129471.2	Q8N2Y8
	RUSC2	NM_001330740.2		c.-620-8441C>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.98C>T	p.Ala33Val	missense	Exon 2 of 12	ENSP00000355177.3	Q8N2Y8
	RUSC2	ENST00000455600.1	TSL:1	c.98C>T	p.Ala33Val	missense	Exon 2 of 12	ENSP00000393922.1	Q8N2Y8
	RUSC2	ENST00000866950.1		c.98C>T	p.Ala33Val	missense	Exon 2 of 12	ENSP00000537009.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000486 AC: 1 AN: 205744 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 24 AN: 1407360 Hom.: 0 Cov.: 29 AF XY: 0.0000173 AC XY: 12 AN XY: 695238

African (AFR) AF: 0.00 AC: 0 AN: 31938

American (AMR) AF: 0.00 AC: 0 AN: 36640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22148

East Asian (EAS) AF: 0.00 AC: 0 AN: 39036

South Asian (SAS) AF: 0.00 AC: 0 AN: 75850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5498

European-Non Finnish (NFE) AF: 0.0000212 AC: 23 AN: 1086528

Other (OTH) AF: 0.0000172 AC: 1 AN: 58068

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.056
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.022	D
Polyphen		0.40	B
Vest4		0.27
MutPred		0.28		Gain of sheet (P = 0.1208)
MVP		0.26
MPC		0.40
ClinPred		0.27	T
GERP RS		3.6
Varity_R		0.079
gMVP		0.18
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1164305616; hg19: chr9-35546616;