1-185099819-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_007212.4(RNF2):​c.766G>C​(p.Val256Leu) 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

Scores

6
11
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.39
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RNF2NM_007212.4 linkuse as main transcriptc.766G>C p.Val256Leu missense_variant 6/7 ENST00000367510.8
RNF2XM_011509851.4 linkuse as main transcriptc.766G>C p.Val256Leu missense_variant 6/7
RNF2XM_011509852.3 linkuse as main transcriptc.766G>C p.Val256Leu missense_variant 6/7
RNF2XM_005245413.4 linkuse as main transcriptc.619G>C p.Val207Leu missense_variant 5/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RNF2ENST00000367510.8 linkuse as main transcriptc.766G>C p.Val256Leu missense_variant 6/71 NM_007212.4 P1Q99496-1
RNF2ENST00000367509.8 linkuse as main transcriptc.550G>C p.Val184Leu missense_variant 5/62 Q99496-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Luo-Schoch-Yamamoto syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The observed missense variant c.766G>C(p.Val256Leu) in RNF2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.766G>C variant is absent in gnomAD Exomes.The amino acid Valine at position 256 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Val256Leu in RNF2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;.
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.80
D;D
MetaSVM
Uncertain
0.61
D
MutationAssessor
Uncertain
2.3
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-2.2
N;N
REVEL
Uncertain
0.57
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.030
D;D
Polyphen
1.0
D;.
Vest4
0.83
MutPred
0.59
Loss of MoRF binding (P = 0.0965);.;
MVP
0.89
MPC
1.9
ClinPred
0.96
D
GERP RS
4.9
Varity_R
0.83
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-185068951; API