rs372632599

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_024570.4(RNASEH2B):c.719C>G(p.Ser240*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

RNASEH2B
NM_024570.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.05

Publications

1 publications found

Variant links:

Genes affected

RNASEH2B (HGNC:25671): (ribonuclease H2 subunit B) RNase H2 is composed of a single catalytic subunit (A) and two non-catalytic subunits (B and C) and specifically degrades the RNA of RNA:DNA hybrids. The protein encoded by this gene is the non-catalytic B subunit of RNase H2, which is thought to play a role in DNA replication. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Aicardi-Goutieres syndrome type 2 (AGS2). [provided by RefSeq, Nov 2008]

RNASEH2B Gene-Disease associations (from GenCC):

Aicardi-Goutieres syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
Aicardi-Goutieres syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RNASEH2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 13-50949483-C-G is Pathogenic according to our data. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50949483-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 582587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2B	NM_024570.4 link	c.719C>G	p.Ser240*	stop_gained	Exon 9 of 11	ENST00000336617.8	NP_078846.2	Q5TBB1-1Q8N451

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2B	ENST00000336617.8 link	c.719C>G	p.Ser240*	stop_gained	Exon 9 of 11	1	NM_024570.4	ENSP00000337623.2		Q5TBB1-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152186

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251184

AF XY:

0.0000221

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461224

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

726920

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

1111562

Other (OTH)

AF:

0.0000166

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.0000565

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 2

Pathogenic:3

Sep 07, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ser240*) in the RNASEH2B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RNASEH2B are known to be pathogenic (PMID: 17846997). This variant is present in population databases (rs372632599, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RNASEH2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 582587). For these reasons, this variant has been classified as Pathogenic. -

Apr 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.25

Eigen_PC

Benign

-0.029

FATHMM_MKL

Benign

0.29

PhyloP100

1.0

Vest4

0.32

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=9/191

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over