chr1-185098265-A-T

Variant names:

• chr1-185098265-A-T
• rs1367415875
• NM_007212.4:c.658A>T
• RNF2 p.Met220Leu

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 (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_007212.4(RNF2):c.658A>T (p.Met220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.M220?: Likely_benign (ClinVar VariationId 2500330, 1 star); p.M220V: Uncertain_significance (ClinVar VariationId 2319271, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF2 NM_007212.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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>T p.Met220Leu	missense	Exon 5 of 7	Prot: NP_009143.1 UniProt:

RNF2 NM_007212.4

MANE Select

HGVSc / HGVSpc.658A>Tp.Met220Leu

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>T p.Met220Leu	missense	Exon 5 of 7	Prot: ENSP00000356480.3 UniProt:
	RNF2 ENST00000942958.1		c.685A>T p.Met229Leu	missense	Exon 5 of 7	Prot: ENSP00000613017.1 UniProt:
	RNF2 ENST00000715230.1		c.658A>T p.Met220Leu	missense	Exon 5 of 7	Prot: ENSP00000520426.1 UniProt:

RNF2 ENST00000367510.8

TSL:1MANE Select

HGVSc / HGVSpc.658A>Tp.Met220Leu

Exon rankExon 5 of 7

missense

Prot: ENSP00000356480.3UniProt: Q99496-1

RNF2 ENST00000942958.1

HGVSc / HGVSpc.685A>Tp.Met229Leu

Exon rankExon 5 of 7

missense

Prot: ENSP00000613017.1UniProt: A0ACI8U9C3

RNF2 ENST00000715230.1

HGVSc / HGVSpc.658A>Tp.Met220Leu

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:34834	Cov:

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.000372	18	48406	0.000470	35	74498

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	17
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.58	D
FuncVEP CTI	Benign	0.00088
GPN-Star LLR	N/A	-5.2
GPN-Star score	N/A	5.2
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.74	T
Mutation Taster	N/A	93/7	polymorphism
MutationAssessor	Benign	0.90	L
PhyloP100	Benign	0.99
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.16
Sift	Benign	0.46	T
Sift4G	Benign	0.55	T
Varity_R	N/A	0.069
VESM-3B	Benign	-2.8

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;

COSMIC: COSV107474472;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar