chr13-50910101-G-A

Position:

• chr13-50910101-G-A

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>A​(p.Asp9Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000763 in 1,310,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (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: 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=0.21254602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASEH2B	NM_024570.4	c.25G>A	p.Asp9Asn	missense_variant	1/11	ENST00000336617.8	NP_078846.2
RNASEH2B-AS1	NR_046552.1	n.230+382C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEH2B	ENST00000336617.8	c.25G>A	p.Asp9Asn	missense_variant	1/11	1	NM_024570.4	ENSP00000337623	P3
RNASEH2B-AS1	ENST00000596992.5	n.112+382C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.63e-7 AC: 1 AN: 1310940 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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: 9.59e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 9 of the RNASEH2B protein (p.Asp9Asn). 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: 1471044). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	Benign	0.18
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.00071	T;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.0	N;N;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.50	N;N;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.055	T;D;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.42	T;T;.;.;.;.;.;.;.;.;.;.
Polyphen		0.20	B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.15
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		0.71
MPC		0.048
ClinPred		0.48	T
GERP RS		2.8
Varity_R		0.11
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-51484237;