dbSNP rs144408326: RNASEH2B:p.Ala287Ser (chr13-50956394-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024570.4(RNASEH2B):c.859G>T(p.Ala287Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00147 in 1,603,568 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 16 hom. )

Consequence

RNASEH2B
NM_024570.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.46

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

Aicardi-Goutieres syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), 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

RNASEH2B links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_024570.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0097846985).

BP6

Variant 13-50956394-G-T is Benign according to our data. Variant chr13-50956394-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0017 (259/152154) while in subpopulation EAS AF = 0.0211 (109/5172). AF 95% confidence interval is 0.0179. There are 2 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNASEH2B	NM_024570.4	MANE Select	c.859G>T	p.Ala287Ser	missense	Exon 11 of 11	NP_078846.2	Q5TBB1-1
RNASEH2B	NM_001411023.1		c.742-3751G>T		intron	N/A	NP_001397952.1	A0A2R8Y883
RNASEH2B	NM_001142279.2		c.741+6889G>T		intron	N/A	NP_001135751.1	Q5TBB1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNASEH2B	ENST00000336617.8	TSL:1 MANE Select	c.859G>T	p.Ala287Ser	missense	Exon 11 of 11	ENSP00000337623.2	Q5TBB1-1
RNASEH2B	ENST00000646960.1		c.859G>T	p.Ala287Ser	missense	Exon 11 of 13	ENSP00000496481.1	A0A2R8Y7R8
RNASEH2B	ENST00000643159.1		c.769G>T	p.Ala257Ser	missense	Exon 13 of 16	ENSP00000495587.1	A0A2R8YEH2

Frequencies

GnomAD3 genomes

AF:

0.00170

AC:

259

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00400

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.0210

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00445

AC:

1054

AN:

236908

AF XY:

0.00393

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.000209

Gnomad EAS exome

AF:

0.0214

Gnomad FIN exome

AF:

0.00137

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00188

GnomAD4 exome

AF:

0.00144

AC:

2097

AN:

1451414

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

1007

AN XY:

721350

show subpopulations

African (AFR)

AF:

0.0000602

AC:

AN:

33220

American (AMR)

AF:

0.0128

AC:

566

AN:

44094

Ashkenazi Jewish (ASJ)

AF:

0.000155

AC:

AN:

25726

East Asian (EAS)

AF:

0.0187

AC:

738

AN:

39452

South Asian (SAS)

AF:

0.00149

AC:

127

AN:

85186

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

52752

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000451

AC:

499

AN:

1105364

Other (OTH)

AF:

0.00159

AC:

AN:

59870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

102

204

307

409

511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00170

AC:

259

AN:

152154

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41502

American (AMR)

AF:

0.00399

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.0211

AC:

109

AN:

5172

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000945

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68008

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00172

Hom.:

Bravo

AF:

0.00242

Asia WGS

AF:

0.00895

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Aicardi-Goutieres syndrome 2 (3)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0098

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.3

PhyloP100

5.5

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.59

Sift

Benign

0.23

Sift4G

Benign

0.19

Varity_R

0.16

gMVP

0.34

Mutation Taster

=83/17

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over