13-50953991-T-C

Position:

• chr13-50953991-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_024570.4(RNASEH2B):​c.822+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,563,916 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (10 hom.)
• Consequence: RNASEH2B NM_024570.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.7763
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.33

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 13-50953991-T-C is Benign according to our data. Variant chr13-50953991-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 312333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-50953991-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00655 (998/152272) while in subpopulation AFR AF= 0.0229 (951/41554). AF 95% confidence interval is 0.0217. There are 14 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASEH2B	NM_024570.4	c.822+6T>C		splice_donor_region_variant, intron_variant		ENST00000336617.8	NP_078846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEH2B	ENST00000336617.8	c.822+6T>C		splice_donor_region_variant, intron_variant		1	NM_024570.4	ENSP00000337623	P3

Frequencies

GnomAD3 genomes AF: 0.00657 AC: 1000 AN: 152154 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

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: 0.000103

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00186 AC: 465 AN: 249436 Hom.: 3 AF XY: 0.00132 AC XY: 178 AN XY: 134814

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000986

GnomAD4 exome AF: 0.000692 AC: 977 AN: 1411644 Hom.: 10 Cov.: 25 AF XY: 0.000603 AC XY: 425 AN XY: 705100

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.00126

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000470

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000244

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00655 AC: 998 AN: 152272 Hom.: 14 Cov.: 32 AF XY: 0.00653 AC XY: 486 AN XY: 74448

Gnomad4 AFR AF: 0.0229

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00339 Hom.: 1

Bravo AF: 0.00783

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Aicardi-Goutieres syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.78
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.060		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: rs76413207; hg19: chr13-51528127;