13-50910101-G-C

Position:

• chr13-50910101-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024570.4(RNASEH2B):​c.25G>C​(p.Asp9His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,310,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D9N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: RNASEH2B NM_024570.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2625807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2B	NM_024570.4	c.25G>C	p.Asp9His	missense_variant	1/11	ENST00000336617.8
RNASEH2B-AS1	NR_046552.1	n.230+382C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2B	ENST00000336617.8	c.25G>C	p.Asp9His	missense_variant	1/11	1	NM_024570.4	P3
RNASEH2B-AS1	ENST00000596992.5	n.112+382C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1310940 Hom.: 0 Cov.: 31 AF XY: 0.00000310 AC XY: 2 AN XY: 644836

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: 0.00000192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aicardi-Goutieres syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 02, 2021

This sequence change replaces aspartic acid with histidine at codon 9 of the RNASEH2B protein (p.Asp9His). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with RNASEH2B-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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	Benign	0.23
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0043	T;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.34	N;N;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.55	N;N;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.011	D;D;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.14	T;T;.;.;.;.;.;.;.;.;.;.
Polyphen		0.64	P;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.19
MutPred		0.39		Gain of catalytic residue at V11 (P = 0);Gain of catalytic residue at V11 (P = 0);Gain of catalytic residue at V11 (P = 0);Gain of catalytic residue at V11 (P = 0);Gain of catalytic residue at V11 (P = 0);Gain of catalytic residue at V11 (P = 0);Gain of catalytic residue at V11 (P = 0);Gain of catalytic residue at V11 (P = 0);Gain of catalytic residue at V11 (P = 0);Gain of catalytic residue at V11 (P = 0);Gain of catalytic residue at V11 (P = 0);Gain of catalytic residue at V11 (P = 0);
MVP		0.73
MPC		0.055
ClinPred		0.44	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.19
gMVP		0.25

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: rs1879259645; hg19: chr13-51484237;