13-50910078-T-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 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. Synonymous variant affecting the same amino acid position has been classified as Likely pathogenic.

• 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
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 10 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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2B	NM_024570.4	MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 11	NP_078846.2	Q5TBB1-1
	RNASEH2B	NM_001411023.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 11	NP_001397952.1	A0A2R8Y883
	RNASEH2B	NM_001142279.2		c.2T>G	p.Met1?	start_lost	Exon 1 of 10	NP_001135751.1	Q5TBB1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2B	ENST00000336617.8	TSL:1 MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000337623.2	Q5TBB1-1
	RNASEH2B	ENST00000646960.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 13	ENSP00000496481.1	A0A2R8Y7R8
	RNASEH2B	ENST00000642721.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 12	ENSP00000495650.1	A0A2R8Y6Y1

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

African (AFR) AF: 0.00 AC: 0 AN: 41360

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67934

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.60	D
PhyloP100		0.88
PROVEAN	Benign	0.39	N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.33	B
Vest4		0.80
MutPred		0.98		Gain of catalytic residue at A3 (P = 2e-04)
MVP		0.84
ClinPred		0.99	D
GERP RS		2.6
PromoterAI		-0.36	Neutral
Varity_R		0.96
gMVP		0.59
Mutation Taster		=24/176	disease causing

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: rs1457494794; hg19: chr13-51484214;