rs865983679

Variant names:

• chr1-185091709-C-T
• rs865983679
• NM_007212.4:c.218C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007212.4(RNF2):​c.218C>T​(p.Ala73Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RNF2 NM_007212.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF2	NM_007212.4	c.218C>T	p.Ala73Val	missense_variant	Exon 3 of 7	ENST00000367510.8	NP_009143.1
RNF2	XM_011509851.4	c.218C>T	p.Ala73Val	missense_variant	Exon 3 of 7		XP_011508153.1
RNF2	XM_011509852.3	c.218C>T	p.Ala73Val	missense_variant	Exon 3 of 7		XP_011508154.1
RNF2	XM_005245413.4	c.71C>T	p.Ala24Val	missense_variant	Exon 2 of 6		XP_005245470.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF2	ENST00000367510.8	c.218C>T	p.Ala73Val	missense_variant	Exon 3 of 7	1	NM_007212.4	ENSP00000356480.3
RNF2	ENST00000367509.8	c.218C>T	p.Ala73Val	missense_variant	Exon 3 of 6	2		ENSP00000356479.4
RNF2	ENST00000453650.2	c.218C>T	p.Ala73Val	missense_variant	Exon 3 of 5	5		ENSP00000400722.2
RNF2	ENST00000498201.1	n.334C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251368 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135856

Gnomad AFR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461762 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.218C>T (p.A73V) alteration is located in exon 3 (coding exon 2) of the RNF2 gene. This alteration results from a C to T substitution at nucleotide position 218, causing the alanine (A) at amino acid position 73 to be replaced by a valine (V). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.064	B;.;.
Vest4		0.72
MutPred		0.54		Loss of catalytic residue at A73 (P = 0.0427);Loss of catalytic residue at A73 (P = 0.0427);Loss of catalytic residue at A73 (P = 0.0427);
MVP		0.87
MPC		0.90
ClinPred		0.95	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.90

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: rs865983679; hg19: chr1-185060841;