13-50910080-G-C

Position:

chr13-50910080-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024570.4(RNASEH2B):c.4G>C(p.Ala2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,463,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

RNASEH2B
NM_024570.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31

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 links:

RNASEH2B-AS1 (HGNC:39967): (RNASEH2B antisense RNA 1)

RNASEH2B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASEH2B	NM_024570.4 linkuse as main transcript	c.4G>C	p.Ala2Pro	missense_variant	1/11	ENST00000336617.8	NP_078846.2
RNASEH2B-AS1	NR_046552.1 linkuse as main transcript	n.230+403C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEH2B	ENST00000336617.8 linkuse as main transcript	c.4G>C	p.Ala2Pro	missense_variant	1/11	1	NM_024570.4	ENSP00000337623	P3	Q5TBB1-1
RNASEH2B-AS1	ENST00000596992.5 linkuse as main transcript	n.112+403C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152056

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.62e-7

AC:

AN:

1311706

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

645434

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.58e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2 of the RNASEH2B protein (p.Ala2Pro). This variant is not present in population databases (gnomAD no frequency). 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: 1512047). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RNASEH2B protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0011

T;.;.;.;.;.;.;.;.;.;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.77

T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.47

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

0.69

N;N;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.29

N;N;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;D;.;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;.;.;.;.;.;.;.;.;.;.

Polyphen

0.84

P;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.45

MutPred

0.36

Gain of catalytic residue at V5 (P = 0);Gain of catalytic residue at V5 (P = 0);Gain of catalytic residue at V5 (P = 0);Gain of catalytic residue at V5 (P = 0);Gain of catalytic residue at V5 (P = 0);Gain of catalytic residue at V5 (P = 0);Gain of catalytic residue at V5 (P = 0);Gain of catalytic residue at V5 (P = 0);Gain of catalytic residue at V5 (P = 0);Gain of catalytic residue at V5 (P = 0);Gain of catalytic residue at V5 (P = 0);Gain of catalytic residue at V5 (P = 0);

MVP

0.75

MPC

0.059

ClinPred

0.61

GERP RS

1.8

Varity_R

0.21

gMVP

0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over