NM_019592.7:c.752C>G

Variant names:

• chr9-101546824-C-G
• rs200163867
• NM_019592.7:c.752C>G
• RNF20 p.Ser251Cys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2BP4

The NM_019592.7(RNF20):c.752C>G (p.Ser251Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000192 (AC=31) in the gnomAD database across 1,613,840 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000191. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: RNF20 NM_019592.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95
• Publications: 1 publications found

Genes affected

RNF20 (HGNC:10062): (ring finger protein 20) The protein encoded by this gene shares similarity with BRE1 of S. cerevisiae. The protein encoded by this human gene is an E3 ubiquitin ligase that regulates chromosome structure by monoubiquitinating histone H2B. This protein acts as a putative tumor suppressor and positively regulates the p53 tumor suppressor as well as numerous histone H2A and H2B genes. In contrast, this protein also suppresses the expression of several protooncogenes and growth-related genes, including many genes that are induced by epidermal growth factor. This gene selectively suppresses the expression of some genes by interfering with chromatin recruitment of transcription elongation factor SII (TFIIS). [provided by RefSeq, Feb 2012]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000191 — very rare for unknown gene (threshold 0.001) — 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 (Supporting).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_019592.7. 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
	RNF20	NM_019592.7	MANE Select	c.752C>G	p.Ser251Cys	missense	Exon 7 of 20	NP_062538.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF20	ENST00000389120.8	TSL:1 MANE Select	c.752C>G	p.Ser251Cys	missense	Exon 7 of 20	ENSP00000373772.3	Q5VTR2
	RNF20	ENST00000888393.1		c.752C>G	p.Ser251Cys	missense	Exon 7 of 20	ENSP00000558452.1	Q5VTR2
	RNF20	ENST00000888394.1		c.752C>G	p.Ser251Cys	missense	Exon 8 of 21	ENSP00000558453.1	Q5VTR2

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: 0.00000658	AC:1	Hom:0	AN:152082	Cov:32
GnomAD2 exomes	AF: 0.00000796	AC:2	Hom:	AN:251332	Cov:
GnomAD4 exome	AF: 0.0000205	AC:30	Hom:0	AN:1461758	Cov:31
GnomAD4 genome	AF: 0.00000658	AC:1	Hom:0	AN:152082	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:2	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28400	0.00	0	28826
Epi25(Epilepsy)	0.00	0	41956	0.0000748	5	66876
SCHEMA(Schizophrenia)	0.00000967	1	103362	0.0000162	3	184644

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	Pathogenic	20
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.022
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.89	D
FuncVEP CTI	Benign	0.015
GPN-Star LLR	N/A	-3.2
GPN-Star score	N/A	3.2
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.73	T
Mutation Taster	N/A	84/16	polymorphism
MutationAssessor	Uncertain	2.0	M
PhyloP100	Benign	2.9
popEVE	Benign	-3.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Benign	0.24
Sift	Benign	0.064	T
Sift4G	Uncertain	0.034	D
Varity_R	N/A	0.075
VESM-3B	Benign	-7.2

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
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.

Other links and lift over

dbSNP: rs200163867;

hg19: chr9-104309106;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar