Genetic Variant RNF212:p.Leu197Gln (chr4-1058378-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001366919.1(RNF212):c.590T>A(p.Leu197Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 144,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. 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. L197R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000021 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

RNF212
NM_001366919.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.17

Publications

7 publications found

Variant links:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.590T>A	p.Leu197Gln	missense	Exon 10 of 12	NP_001353848.1	A0A8V8TN20
	RNF212	NM_001366918.1		c.590T>A	p.Leu197Gln	missense	Exon 10 of 11	NP_001353847.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF212	ENST00000698262.1		c.590T>A	p.Leu197Gln	missense	Exon 10 of 12	ENSP00000513634.1	A0A8V8TN20
RNF212	ENST00000503206.5	TSL:3	n.163T>A		non_coding_transcript_exon	Exon 4 of 5
RNF212	ENST00000505693.5	TSL:5	n.517T>A		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes

AF:

0.0000139

AC:

AN:

144380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000225

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000155

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000210

AC:

AN:

286032

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

132366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

3900

American (AMR)

AF:

0.00

AC:

AN:

380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1492

East Asian (EAS)

AF:

0.00

AC:

AN:

1466

South Asian (SAS)

AF:

0.00

AC:

AN:

5154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1616

European-Non Finnish (NFE)

AF:

0.0000229

AC:

AN:

262302

Other (OTH)

AF:

0.00

AC:

AN:

9236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000139

AC:

AN:

144380

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

70256

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40106

American (AMR)

AF:

0.00

AC:

AN:

14436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3224

East Asian (EAS)

AF:

0.00

AC:

AN:

4686

South Asian (SAS)

AF:

0.000225

AC:

AN:

4436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

64514

Other (OTH)

AF:

0.00

AC:

AN:

1964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00

Hom.:

4498

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.2

(source)

DANN

Benign

0.68

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism

(source)

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