Variant 1-185098250-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_007212.4(RNF2):c.643G>T(p.Ala215Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

RNF2
NM_007212.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52

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]

RNF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07058188).

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RNF2	NM_007212.4 linkuse as main transcript	c.643G>T	p.Ala215Ser	missense_variant	5/7	ENST00000367510.8
RNF2	XM_011509851.4 linkuse as main transcript	c.643G>T	p.Ala215Ser	missense_variant	5/7
RNF2	XM_011509852.3 linkuse as main transcript	c.643G>T	p.Ala215Ser	missense_variant	5/7
RNF2	XM_005245413.4 linkuse as main transcript	c.496G>T	p.Ala166Ser	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF2	ENST00000367510.8 linkuse as main transcript	c.643G>T	p.Ala215Ser	missense_variant	5/7	1	NM_007212.4	P1	Q99496-1
RNF2	ENST00000367509.8 linkuse as main transcript	c.427G>T	p.Ala143Ser	missense_variant	4/6	2			Q99496-2
RNF2	ENST00000453650.2 linkuse as main transcript	c.643G>T	p.Ala215Ser	missense_variant	5/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

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

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251338

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.643G>T (p.A215S) alteration is located in exon 5 (coding exon 4) of the RNF2 gene. This alteration results from a G to T substitution at nucleotide position 643, causing the alanine (A) at amino acid position 215 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.28

T;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.24

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.071

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-0.81

N;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.020

N;N;N

REVEL

Benign

0.23

Sift

Benign

0.98

T;T;T

Sift4G

Benign

0.73

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.20

MVP

0.54

MPC

0.82

ClinPred

0.13

GERP RS

3.7

Varity_R

0.028

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over