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 (★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: RNASEH2B NM_024570.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152056 Hom.: 0 Cov.: 32

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: 1 AN: 1311706 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 645434

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: 1 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74268

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

Submissions by phenotype

Aicardi-Goutieres syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0011	T;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.69	N;N;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.76	T
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	D
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

Other links and lift over

dbSNP: rs1161853513; hg19: chr13-51484216;