RNF2 p.Met220Val

Variant names:

• chr1-185098265-A-G
• rs1367415875
• NM_007212.4:c.658A>G
• RNF2 p.Met220Val

Your query was ambiguous. Multiple possible variants found:

• chr1-185098265-A-G
• chr1-185098265-ATG-GTA
• chr1-185098265-ATG-GTC
• chr1-185098265-ATG-GTT

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingB3_Supporting

The NM_007212.4(RNF2):c.658A>G (p.Met220Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene RNF2 is a known oncogene (CancerMine: 14 oncogene citations). The variant allele was found at a cumulative frequency of 0.0000149 (AC=24) in the gnomAD database across 1,613,976 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000054. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.M220?: Likely_benign (ClinVar VariationId 2500330, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RNF2 NM_007212.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.993
• Publications: 0 publications found

Genes affected

RNF2 (HGNC:10061): (ring finger protein 2) Polycomb group (PcG) of proteins form the multiprotein complexes that are important for the transcription repression of various genes involved in development and cell proliferation. The protein encoded by this gene is one of the PcG proteins. It has been shown to interact with, and suppress the activity of, transcription factor CP2 (TFCP2/CP2). Studies of the mouse counterpart suggested the involvement of this gene in the specification of anterior-posterior axis, as well as in cell proliferation in early development. This protein was also found to interact with huntingtin interacting protein 2 (HIP2), an ubiquitin-conjugating enzyme, and possess ubiquitin ligase activity. [provided by RefSeq, Jul 2008]

RNF2 Gene-Disease associations (from GenCC):

• Luo-Schoch-Yamamoto syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000054 — very rare (O3 supporting [+1])
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007212.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RNF2 NM_007212.4	MANE Select	c.658A>G p.Met220Val	missense	Exon 5 of 7	Prot: NP_009143.1 UniProt:

RNF2 NM_007212.4

MANE Select

HGVSc / HGVSpc.658A>Gp.Met220Val

Exon rankExon 5 of 7

missense

Prot: NP_009143.1UniProt: Q99496-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RNF2 ENST00000367510.8	TSL:1MANE Select	c.658A>G p.Met220Val	missense	Exon 5 of 7	Prot: ENSP00000356480.3 UniProt:
	RNF2 ENST00000942958.1		c.685A>G p.Met229Val	missense	Exon 5 of 7	Prot: ENSP00000613017.1 UniProt:
	RNF2 ENST00000715230.1		c.658A>G p.Met220Val	missense	Exon 5 of 7	Prot: ENSP00000520426.1 UniProt:

RNF2 ENST00000367510.8

TSL:1MANE Select

HGVSc / HGVSpc.658A>Gp.Met220Val

Exon rankExon 5 of 7

missense

Prot: ENSP00000356480.3UniProt: Q99496-1

RNF2 ENST00000942958.1

HGVSc / HGVSpc.685A>Gp.Met229Val

Exon rankExon 5 of 7

missense

Prot: ENSP00000613017.1UniProt: A0ACI8U9C3

RNF2 ENST00000715230.1

HGVSc / HGVSpc.658A>Gp.Met220Val

Exon rankExon 5 of 7

missense

Prot: ENSP00000520426.1UniProt: Q99496-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000197	AC:3	Hom:0	AN:152248	Cov:32
GnomAD2 exomes	AF: 0.0000199	AC:5	Hom:	AN:251340	Cov:
GnomAD4 exome	AF: 0.0000144	AC:21	Hom:0	AN:1461728	Cov:32
GnomAD4 genome	AF: 0.0000197	AC:3	Hom:0	AN:152248	Cov:32
TOPMed (Bravo)	AF: 0.0000113	AC:3	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000287	AC:1	Hom:0	AN:34834	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000477	2	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000387	4	103332	0.0000163	3	184612

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	17
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.79
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.54	D
FuncVEP CTI	Benign	0.0010
GPN-Star LLR	N/A	-5.0
GPN-Star score	N/A	5.0
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.72	T
Mutation Taster	N/A	92/8	polymorphism
MutationAssessor	Benign	0.90	L
PhyloP100	Benign	0.99
popEVE	Benign	-3.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.18
Sift	Benign	0.39	T
Sift4G	Benign	0.46	T
Varity_R	N/A	0.060
VESM-3B	Benign	-3.0

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1367415875;

hg19: chr1-185067397;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar