chr13-50909867-G-C

Position:

• chr13-50909867-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024570.4(RNASEH2B):​c.-210G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0273 in 433,218 control chromosomes in the GnomAD database, including 203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (79 hom., cov: 33)
  • Exomes 𝑓: 0.026 (124 hom.)
• Consequence: RNASEH2B NM_024570.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.119

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 13-50909867-G-C is Benign according to our data. Variant chr13-50909867-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 312324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0294 (4481/152282) while in subpopulation SAS AF= 0.0456 (220/4826). AF 95% confidence interval is 0.0407. There are 79 homozygotes in gnomad4. There are 2213 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 79 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASEH2B	NM_024570.4	c.-210G>C		5_prime_UTR_variant	1/11	ENST00000336617.8	NP_078846.2
RNASEH2B-AS1	NR_046552.1	n.230+616C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEH2B	ENST00000336617.8	c.-210G>C		5_prime_UTR_variant	1/11	1	NM_024570.4	ENSP00000337623	P3
RNASEH2B-AS1	ENST00000596992.5	n.112+616C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4480 AN: 152168 Hom.: 79 Cov.: 33

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0462

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.0253

GnomAD4 exome AF: 0.0261 AC: 7340 AN: 280936 Hom.: 124 Cov.: 4 AF XY: 0.0272 AC XY: 4015 AN XY: 147524

Gnomad4 AFR exome AF: 0.0387

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.000413

Gnomad4 SAS exome AF: 0.0493

Gnomad4 FIN exome AF: 0.0312

Gnomad4 NFE exome AF: 0.0267

Gnomad4 OTH exome AF: 0.0250

GnomAD4 genome AF: 0.0294 AC: 4481 AN: 152282 Hom.: 79 Cov.: 33 AF XY: 0.0297 AC XY: 2213 AN XY: 74462

Gnomad4 AFR AF: 0.0405

Gnomad4 AMR AF: 0.0151

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.0456

Gnomad4 FIN AF: 0.0327

Gnomad4 NFE AF: 0.0277

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0276 Hom.: 7

Bravo AF: 0.0279

Asia WGS AF: 0.0200 AC: 70 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Aicardi-Goutieres syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.4
DANN	Benign	0.81

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: rs112702177; hg19: chr13-51484003;