12-123423084-C-G

Variant names:

• chr12-123423084-C-G
• rs1175669490
• NM_145058.3:c.565G>C

Variant summary

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

The NM_145058.3(RILPL2):​c.565G>C​(p.Ala189Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,930 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A189T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RILPL2 NM_145058.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.476
• Publications: 0 publications found

Genes affected

RILPL2 (HGNC:28787): (Rab interacting lysosomal protein like 2) This gene encodes a protein that contains a rab-interacting lysosomal protein-like domain. This protein may be involved in regulating lysosome morphology. This protein may also be a target for the Hepatitis C virus and assist in viral replication. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

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=0.06388551).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145058.3. 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
	RILPL2	NM_145058.3	MANE Select	c.565G>C	p.Ala189Pro	missense	Exon 3 of 4	NP_659495.1	Q969X0
	RILPL2	NR_130703.2		n.677G>C		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RILPL2	ENST00000280571.10	TSL:1 MANE Select	c.565G>C	p.Ala189Pro	missense	Exon 3 of 4	ENSP00000280571.8	Q969X0
	RILPL2	ENST00000718483.1		c.565G>C	p.Ala189Pro	missense	Exon 3 of 4	ENSP00000520843.1	A0ABB0MVJ7
	RILPL2	ENST00000718482.1		c.565G>C	p.Ala189Pro	missense	Exon 3 of 4	ENSP00000520842.1	A0ABB0MVH7

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151930 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111912

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151930 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74170

African (AFR) AF: 0.0000242 AC: 1 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

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

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.7
DANN	Benign	0.91
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.48
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.66	N
REVEL	Benign	0.087
Sift	Benign	0.20	T
Sift4G	Benign	0.36	T
Polyphen		0.0060	B
Vest4		0.14
MutPred		0.17		Gain of glycosylation at A189 (P = 0.037)
MVP		0.13
MPC		0.68
ClinPred		0.040	T
GERP RS		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.15
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: rs1175669490; hg19: chr12-123907631;