rs761469213

Variant names:

• chr7-5623164-C-G
• rs761469213
• NM_207111.4:c.2468G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-5623164-C-G
• chr7-5623164-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_207111.4(RNF216):​c.2468G>C​(p.Arg823Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,405,402 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R823C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RNF216 NM_207111.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.37
• Publications: 0 publications found

Genes affected

RNF216 (HGNC:21698): (ring finger protein 216) This gene encodes a cytoplasmic protein which specifically colocalizes and interacts with the serine/threonine protein kinase, receptor-interacting protein (RIP). Zinc finger domains of the encoded protein are required for its interaction with RIP and for inhibition of TNF- and IL1-induced NF-kappa B activation pathways. The encoded protein may also function as an E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes and transfers it to substrates. Several alternatively spliced transcript variants have been described for this locus but the full-length natures of only some are known. [provided by RefSeq, Jul 2008]

RNF216 Gene-Disease associations (from GenCC):

• cerebellar ataxia-hypogonadism syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207111.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF216	NM_207111.4	MANE Select	c.2468G>C	p.Arg823Pro	missense	Exon 17 of 17	NP_996994.1
	RNF216	NM_001377156.1		c.2297G>C	p.Arg766Pro	missense	Exon 18 of 18	NP_001364085.1
	RNF216	NM_207116.3		c.2297G>C	p.Arg766Pro	missense	Exon 17 of 17	NP_996999.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF216	ENST00000389902.8	TSL:1 MANE Select	c.2468G>C	p.Arg823Pro	missense	Exon 17 of 17	ENSP00000374552.3
	RNF216	ENST00000425013.6	TSL:1	c.2297G>C	p.Arg766Pro	missense	Exon 17 of 17	ENSP00000404602.2
	RNF216	ENST00000389900.8	TSL:1	n.*1585G>C		non_coding_transcript_exon	Exon 16 of 16	ENSP00000374550.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1405402 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 690634

African (AFR) AF: 0.00 AC: 0 AN: 32268

American (AMR) AF: 0.00 AC: 0 AN: 39614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22852

East Asian (EAS) AF: 0.00 AC: 0 AN: 38894

South Asian (SAS) AF: 0.00 AC: 0 AN: 78686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5488

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078180

Other (OTH) AF: 0.00 AC: 0 AN: 57870

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.24		Loss of MoRF binding (P = 5e-04)
MVP		0.69
MPC		0.21
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.85
gMVP		0.74
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs761469213; hg19: chr7-5662795;