rs146451037

Positions:

• chr13-50943339-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_024570.4(RNASEH2B):​c.455A>G​(p.Asn152Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000902 in 1,600,830 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (2 hom.)
• Consequence: RNASEH2B NM_024570.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.808

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010262281).
• BP6: Variant 13-50943339-A-G is Benign according to our data. Variant chr13-50943339-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 312330.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}. Variant chr13-50943339-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASEH2B	NM_024570.4	c.455A>G	p.Asn152Ser	missense_variant	6/11	ENST00000336617.8	NP_078846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEH2B	ENST00000336617.8	c.455A>G	p.Asn152Ser	missense_variant	6/11	1	NM_024570.4	ENSP00000337623.2

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000852

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000754 AC: 189 AN: 250776 Hom.: 0 AF XY: 0.000797 AC XY: 108 AN XY: 135514

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000296

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000932 AC: 1350 AN: 1448554 Hom.: 2 Cov.: 28 AF XY: 0.000980 AC XY: 707 AN XY: 721468

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.00411

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000292

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74470

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00114 Hom.: 1

Bravo AF: 0.000646

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000791 AC: 96

EpiCase AF: 0.00125

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 13, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -

Aicardi-Goutieres syndrome 2 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.50
DEOGEN2	Benign	0.25	T;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.82	T;T;D;D;T;T;T;T;T;T;T;D;T;T;.;.;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.20	N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.48	N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.74	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	1.0	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0030	B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.049
MVP		0.69
MPC		0.043
ClinPred		0.00056	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.037
gMVP		0.063

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

Other links and lift over

dbSNP: rs146451037; hg19: chr13-51517475;