1-185091700-G-A

Position:

• chr1-185091700-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_007212.4(RNF2):​c.209G>A​(p.Arg70His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF2 NM_007212.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.37

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a mutagenesis_site Loss of ubiquitin ligase activity on histone H2A. (size 0) in uniprot entity RING2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF2	NM_007212.4	c.209G>A	p.Arg70His	missense_variant	3/7	ENST00000367510.8	NP_009143.1
RNF2	XM_011509851.4	c.209G>A	p.Arg70His	missense_variant	3/7		XP_011508153.1
RNF2	XM_011509852.3	c.209G>A	p.Arg70His	missense_variant	3/7		XP_011508154.1
RNF2	XM_005245413.4	c.62G>A	p.Arg21His	missense_variant	2/6		XP_005245470.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF2	ENST00000367510.8	c.209G>A	p.Arg70His	missense_variant	3/7	1	NM_007212.4	ENSP00000356480	P1
RNF2	ENST00000367509.8	c.209G>A	p.Arg70His	missense_variant	3/6	2		ENSP00000356479
RNF2	ENST00000453650.2	c.209G>A	p.Arg70His	missense_variant	3/5	5		ENSP00000400722
RNF2	ENST00000498201.1	n.325G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Luo-Schoch-Yamamoto syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 19, 2021

- -

RNF2-associated neurodevelopmental condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

May 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.82
MutPred		0.62		Loss of ubiquitination at K65 (P = 0.1191);Loss of ubiquitination at K65 (P = 0.1191);Loss of ubiquitination at K65 (P = 0.1191);
MVP		0.96
MPC		1.9
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs1651767648; hg19: chr1-185060832;