Genetic Variant RNASEH2B:p.Ala287Pro (chr13-50956394-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000336617.8(RNASEH2B):c.859G>C(p.Ala287Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A287S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

RNASEH2B
ENST00000336617.8 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
Aicardi-Goutieres syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RNASEH2B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000336617.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RNASEH2B	NM_024570.4	MANE Select	c.859G>C	p.Ala287Pro	missense	Exon 11 of 11	NP_078846.2
RNASEH2B	NM_001411023.1		c.742-3751G>C		intron	N/A	NP_001397952.1
RNASEH2B	NM_001142279.2		c.741+6889G>C		intron	N/A	NP_001135751.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RNASEH2B	ENST00000336617.8	TSL:1 MANE Select	c.859G>C	p.Ala287Pro	missense	Exon 11 of 11	ENSP00000337623.2
RNASEH2B	ENST00000646960.1		c.859G>C	p.Ala287Pro	missense	Exon 11 of 13	ENSP00000496481.1
RNASEH2B	ENST00000643159.1		c.769G>C	p.Ala257Pro	missense	Exon 13 of 16	ENSP00000495587.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

PhyloP100

5.5

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.76

Sift

Uncertain

0.014

Sift4G

Uncertain

0.035

Polyphen

1.0

Vest4

0.45

MutPred

0.53

Loss of stability (P = 0.0131)

MVP

0.99

MPC

0.37

ClinPred

0.98

GERP RS

6.1

Varity_R

0.76

gMVP

0.57

Mutation Taster

=42/58

disease causing

(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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over