rs35416748

chr13-50929494-G-Achr13-50929494-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024570.4(RNASEH2B):c.156G>A(p.Leu52=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,613,016 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (19 hom.)
• Consequence: RNASEH2B NM_024570.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.41

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 13-50929494-G-A is Benign according to our data. Variant chr13-50929494-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50929494-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00899 (1368/152216) while in subpopulation AFR AF= 0.0313 (1300/41532). AF 95% confidence interval is 0.0299. There are 18 homozygotes in gnomad4. There are 657 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2B	NM_024570.4	c.156G>A	p.Leu52=	synonymous_variant	3/11	ENST00000336617.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2B	ENST00000336617.8	c.156G>A	p.Leu52=	synonymous_variant	3/11	1	NM_024570.4	P3

Frequencies

GnomAD3 genomes AF: 0.00896 AC: 1363 AN: 152098 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00256 AC: 642 AN: 251240 Hom.: 9 AF XY: 0.00184 AC XY: 250 AN XY: 135796

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000879 AC: 1284 AN: 1460800 Hom.: 19 Cov.: 30 AF XY: 0.000771 AC XY: 560 AN XY: 726762

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00899 AC: 1368 AN: 152216 Hom.: 18 Cov.: 32 AF XY: 0.00883 AC XY: 657 AN XY: 74426

Gnomad4 AFR AF: 0.0313

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00378 Hom.: 4

Bravo AF: 0.0104

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	5.5
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs35416748; hg19: chr13-51503630;