13-50953991-T-G

Variant names:

• chr13-50953991-T-G
• rs76413207
• NM_024570.4:c.822+6T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024570.4(RNASEH2B):​c.822+6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,411,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RNASEH2B NM_024570.4 splice_region, intron
• Scores: Splicing: ADA: 0.7366
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33
• Publications: 0 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 Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• RNASEH2B-related type 1 interferonopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31901628).

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.822+6T>G		splice_region intron	N/A	NP_078846.2	Q5TBB1-1
	RNASEH2B	NM_001411023.1		c.741+4486T>G		intron	N/A	NP_001397952.1	A0A2R8Y883
	RNASEH2B	NM_001142279.2		c.741+4486T>G		intron	N/A	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.822+6T>G		splice_region intron	N/A	ENSP00000337623.2	Q5TBB1-1
	RNASEH2B	ENST00000616907.2	TSL:3	c.828T>G	p.Cys276Trp	missense	Exon 10 of 10	ENSP00000482701.2	A0A087WZJ6
	RNASEH2B	ENST00000646960.1		c.822+6T>G		splice_region intron	N/A	ENSP00000496481.1	A0A2R8Y7R8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1411658 Hom.: 0 Cov.: 25 AF XY: 0.00000142 AC XY: 1 AN XY: 705106

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32308

American (AMR) AF: 0.00 AC: 0 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25836

East Asian (EAS) AF: 0.00 AC: 0 AN: 39448

South Asian (SAS) AF: 0.00 AC: 0 AN: 85192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 9.38e-7 AC: 1 AN: 1066598

Other (OTH) AF: 0.00 AC: 0 AN: 58704

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.97
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.32	T
PhyloP100		2.3
GERP RS		5.6
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.74
dbscSNV1_RF	Benign	0.34
SpliceAI score (max)		0.18		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: rs76413207; hg19: chr13-51528127;