NM_024570.4:c.2T>G

Variant names:

• chr13-50910078-T-G
• rs1457494794
• NM_024570.4:c.2T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_024570.4(RNASEH2B):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RNASEH2B NM_024570.4 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.881

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 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 31 codons. Genomic position: 50927433. Lost 0.097 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2B	NM_024570.4	c.2T>G	p.Met1?	start_lost	Exon 1 of 11	ENST00000336617.8	NP_078846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2B	ENST00000336617.8	c.2T>G	p.Met1?	start_lost	Exon 1 of 11	1	NM_024570.4	ENSP00000337623.2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151848 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 Cov.: 31

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151848 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74142

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.0028	T;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.60	D
PROVEAN	Benign	0.39	N;N;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;.;.;.
Polyphen		0.33	B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.80
MutPred		0.98		Gain of catalytic residue at A3 (P = 2e-04);Gain of catalytic residue at A3 (P = 2e-04);Gain of catalytic residue at A3 (P = 2e-04);Gain of catalytic residue at A3 (P = 2e-04);Gain of catalytic residue at A3 (P = 2e-04);Gain of catalytic residue at A3 (P = 2e-04);Gain of catalytic residue at A3 (P = 2e-04);Gain of catalytic residue at A3 (P = 2e-04);Gain of catalytic residue at A3 (P = 2e-04);Gain of catalytic residue at A3 (P = 2e-04);Gain of catalytic residue at A3 (P = 2e-04);Gain of catalytic residue at A3 (P = 2e-04);
MVP		0.84
ClinPred		0.99	D
GERP RS		2.6
Varity_R		0.96
gMVP		0.59

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: rs1457494794; hg19: chr13-51484214;