Genetic Variant RNF212:p.Arg257ProfsTer20 (chr4-1056882-C-CG) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001366919.1(RNF212):c.769dupC(p.Arg257ProfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 985,460 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 3 hom. )

Consequence

RNF212
NM_001366919.1 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.10

Publications

0 publications found

Variant links:

COSMIC-nc: COSV101540041

Genes affected

RNF212 (HGNC:27729): (ring finger protein 212) This gene encodes a RING finger protein that may function as a ubiquitin ligase. The encoded protein may be involved in meiotic recombination. This gene is located within a linkage disequilibrium block and polymorphisms in this gene may influence recombination rates. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

RNF212 Gene-Disease associations (from GenCC):

spermatogenic failure 62
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

RNF212 links:

ENSG00000294272 (HGNC:):

ENSG00000294272 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366919.1. 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
	RNF212	NM_001366919.1		c.769dupC	p.Arg257ProfsTer20	frameshift	Exon 11 of 12	NP_001353848.1	A0A8V8TN20
	RNF212	NM_001366918.1		c.648-380dupC		intron	N/A	NP_001353847.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF212	ENST00000698262.1		c.769dupC	p.Arg257ProfsTer20	frameshift	Exon 11 of 12	ENSP00000513634.1	A0A8V8TN20
RNF212	ENST00000505693.5	TSL:5	n.696dupC		non_coding_transcript_exon	Exon 5 of 6
RNF212	ENST00000508633.5	TSL:3	n.351dupC		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00335

AC:

509

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000943

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00321

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00579

Gnomad OTH

AF:

0.00287

GnomAD4 exome

AF:

0.00443

AC:

3692

AN:

833332

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

1684

AN XY:

385050

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

15816

American (AMR)

AF:

0.00

AC:

AN:

990

Ashkenazi Jewish (ASJ)

AF:

0.00117

AC:

AN:

5128

East Asian (EAS)

AF:

0.00

AC:

AN:

3622

South Asian (SAS)

AF:

0.00182

AC:

AN:

16502

European-Finnish (FIN)

AF:

0.00977

AC:

AN:

614

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

3248

European-Non Finnish (NFE)

AF:

0.00463

AC:

3521

AN:

760016

Other (OTH)

AF:

0.00445

AC:

122

AN:

27396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

170

339

509

678

848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<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:

0.00335

AC:

510

AN:

152128

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

232

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000940

AC:

AN:

41482

American (AMR)

AF:

0.00118

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00187

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00321

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00580

AC:

394

AN:

67986

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00212

Hom.:

Bravo

AF:

0.00277

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spermatogenic failure 62 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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