Genetic Variant RNF216:p.Pro919Pro (chr7-5622875-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_207111.4(RNF216):c.2757G>A(p.Pro919Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000587 in 1,602,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

RNF216
NM_207111.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -5.72

Publications

0 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

RNF216 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 7-5622875-C-T is Benign according to our data. Variant chr7-5622875-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 740477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.72 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000591 (90/152336) while in subpopulation AMR AF = 0.00183 (28/15306). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF216	NM_207111.4	MANE Select	c.2757G>A	p.Pro919Pro	synonymous	Exon 17 of 17	NP_996994.1	Q9NWF9-1
RNF216	NM_001377156.1		c.2586G>A	p.Pro862Pro	synonymous	Exon 18 of 18	NP_001364085.1	Q9NWF9-2
RNF216	NM_207116.3		c.2586G>A	p.Pro862Pro	synonymous	Exon 17 of 17	NP_996999.1	Q9NWF9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF216	ENST00000389902.8	TSL:1 MANE Select	c.2757G>A	p.Pro919Pro	synonymous	Exon 17 of 17	ENSP00000374552.3	Q9NWF9-1
RNF216	ENST00000425013.6	TSL:1	c.2586G>A	p.Pro862Pro	synonymous	Exon 17 of 17	ENSP00000404602.2	Q9NWF9-2
RNF216	ENST00000389900.8	TSL:1	n.*1874G>A		non_coding_transcript_exon	Exon 16 of 16	ENSP00000374550.4	F8W6D1

Frequencies

GnomAD3 genomes

AF:

0.000591

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

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:

0.000691

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000319

AC:

AN:

247410

AF XY:

0.000345

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000727

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000401

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000587

AC:

851

AN:

1449774

Hom.:

Cov.:

AF XY:

0.000556

AC XY:

400

AN XY:

718786

show subpopulations

African (AFR)

AF:

0.000300

AC:

AN:

33326

American (AMR)

AF:

0.000653

AC:

AN:

44400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25842

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39384

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51996

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.000710

AC:

784

AN:

1103582

Other (OTH)

AF:

0.000384

AC:

AN:

59838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

131

174

218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000591

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41586

American (AMR)

AF:

0.00183

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68020

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000345

Hom.:

Bravo

AF:

0.000514

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.026

(source)

DANN

Benign

0.76

PhyloP100

-5.7

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over