Variant 13-50910078-TG-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_024570.4(RNASEH2B):c.4del(p.Ala2?) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000763 in 1,311,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

RNASEH2B
NM_024570.4 frameshift, start_lost

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.31

Variant links:

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 links:

RNASEH2B-AS1 (HGNC:39967): (RNASEH2B antisense RNA 1)

RNASEH2B-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 68 pathogenic variants in the truncated region.

PS1

Another start lost variant in NM_024570.4 (RNASEH2B) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 661979

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-50910078-TG-T is Pathogenic according to our data. Variant chr13-50910078-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 1451439.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2B	NM_024570.4 linkuse as main transcript	c.4del	p.Ala2?	frameshift_variant, start_lost	1/11	ENST00000336617.8
RNASEH2B-AS1	NR_046552.1 linkuse as main transcript	n.230+404del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2B	ENST00000336617.8 linkuse as main transcript	c.4del	p.Ala2?	frameshift_variant, start_lost	1/11	1	NM_024570.4	P3	Q5TBB1-1
RNASEH2B-AS1	ENST00000596992.5 linkuse as main transcript	n.112+404del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.63e-7

AC:

AN:

1311206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

645210

show subpopulations

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

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1451439). This variant has not been reported in the literature in individuals affected with RNASEH2B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala2Profs*23) in the RNASEH2B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RNASEH2B are known to be pathogenic (PMID: 17846997). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over