13-50910116-C-G

Variant names:

• chr13-50910116-C-G
• rs900876937
• NM_024570.4:c.40C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024570.4(RNASEH2B):​c.40C>G​(p.Arg14Gly) 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 1,306,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14Q) 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: Not reported in ClinVar
• Conservation: PhyloP100: -0.153
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16788116).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024570.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2B	NM_024570.4	MANE Select	c.40C>G	p.Arg14Gly	missense	Exon 1 of 11	NP_078846.2
	RNASEH2B	NM_001411023.1		c.40C>G	p.Arg14Gly	missense	Exon 1 of 11	NP_001397952.1
	RNASEH2B	NM_001142279.2		c.40C>G	p.Arg14Gly	missense	Exon 1 of 10	NP_001135751.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2B	ENST00000336617.8	TSL:1 MANE Select	c.40C>G	p.Arg14Gly	missense	Exon 1 of 11	ENSP00000337623.2
	RNASEH2B	ENST00000646960.1		c.40C>G	p.Arg14Gly	missense	Exon 1 of 13	ENSP00000496481.1
	RNASEH2B	ENST00000642721.1		c.40C>G	p.Arg14Gly	missense	Exon 1 of 12	ENSP00000495650.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1306918 Hom.: 0 Cov.: 31 AF XY: 0.00000156 AC XY: 1 AN XY: 642356

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26078

American (AMR) AF: 0.00 AC: 0 AN: 22816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22100

East Asian (EAS) AF: 0.0000710 AC: 2 AN: 28164

South Asian (SAS) AF: 0.00 AC: 0 AN: 68754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3996

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1039460

Other (OTH) AF: 0.00 AC: 0 AN: 53750

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.15
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.25
Sift	Benign	0.36	T
Sift4G	Benign	0.27	T
Polyphen		0.38	B
Vest4		0.27
MutPred		0.59		Gain of catalytic residue at V11 (P = 0)
MVP		0.60
MPC		0.12
ClinPred		0.11	T
GERP RS		0.063
PromoterAI		-0.0030	Neutral
Varity_R		0.24
gMVP		0.17
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs900876937; hg19: chr13-51484252;