chr9-35546675-A-C

Variant names:

• chr9-35546675-A-C
• rs771426449
• NM_014806.5:c.154A>C

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.154A>C​(p.Ile52Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000326 in 1,566,032 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 (★). Synonymous variant affecting the same amino acid position (i.e. I52I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: RUSC2 NM_014806.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.994
• 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=0.03136909).

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.154A>C	p.Ile52Leu	missense	Exon 2 of 12	NP_055621.2	Q8N2Y8
	RUSC2	NM_001135999.2		c.154A>C	p.Ile52Leu	missense	Exon 2 of 12	NP_001129471.2	Q8N2Y8
	RUSC2	NM_001330740.2		c.-620-8385A>C		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.154A>C	p.Ile52Leu	missense	Exon 2 of 12	ENSP00000355177.3	Q8N2Y8
	RUSC2	ENST00000455600.1	TSL:1	c.154A>C	p.Ile52Leu	missense	Exon 2 of 12	ENSP00000393922.1	Q8N2Y8
	RUSC2	ENST00000866950.1		c.154A>C	p.Ile52Leu	missense	Exon 2 of 12	ENSP00000537009.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000963 AC: 2 AN: 207776 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: 0.0000207

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000347 AC: 49 AN: 1413830 Hom.: 0 Cov.: 29 AF XY: 0.0000315 AC XY: 22 AN XY: 698866

African (AFR) AF: 0.00 AC: 0 AN: 32180

American (AMR) AF: 0.00 AC: 0 AN: 37600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22460

East Asian (EAS) AF: 0.00 AC: 0 AN: 39286

South Asian (SAS) AF: 0.00 AC: 0 AN: 76926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.0000404 AC: 44 AN: 1089796

Other (OTH) AF: 0.0000858 AC: 5 AN: 58270

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000604 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000825 AC: 1

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	0.080
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.72
DANN	Benign	0.56
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.27	N
PhyloP100		-0.99
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.029
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.14		Gain of catalytic residue at I52 (P = 0.0329)
MVP		0.17
MPC		0.16
ClinPred		0.022	T
GERP RS		-3.6
Varity_R		0.032
gMVP		0.11
Mutation Taster		=93/7	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: rs771426449; hg19: chr9-35546672;