Genetic Variant RNASEH2C:p.Lys90Arg (chr11-65720321-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_032193.4(RNASEH2C):c.269A>G(p.Lys90Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. K90M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RNASEH2C
NM_032193.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.855

Publications

0 publications found

Variant links:

Genes affected

RNASEH2C (HGNC:24116): (ribonuclease H2 subunit C) This gene encodes a ribonuclease H subunit that can cleave ribonucleotides from RNA:DNA duplexes. Mutations in this gene cause Aicardi-Goutieres syndrome-3, a disease that causes severe neurologic dysfunction. A pseudogene for this gene has been identified on chromosome Y, near the sex determining region Y (SRY) gene. [provided by RefSeq, Jul 2008]

RNASEH2C Gene-Disease associations (from GenCC):

Aicardi-Goutieres syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
Aicardi-Goutieres syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RNASEH2C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a chain Ribonuclease H2 subunit C (size 163) in uniprot entity RNH2C_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_032193.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05488023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2C	NM_032193.4 link	c.269A>G	p.Lys90Arg	missense_variant	Exon 2 of 4	ENST00000308418.10	NP_115569.2	Q8TDP1A0A024R5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2C	ENST00000308418.10 link	c.269A>G	p.Lys90Arg	missense_variant	Exon 2 of 4	1	NM_032193.4	ENSP00000308193.5		Q8TDP1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451048

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33400

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

31024

South Asian (SAS)

AF:

0.00

AC:

AN:

85658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111228

Other (OTH)

AF:

0.00

AC:

AN:

59828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

3.1

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.28

.;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.055

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.58

N;.

PhyloP100

0.85

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.90

N;N

REVEL

Benign

0.14

Sift

Benign

0.41

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.018

B;.

Vest4

0.14

MutPred

0.44

Loss of methylation at K90 (P = 0.0048);Loss of methylation at K90 (P = 0.0048);

MVP

0.25

MPC

0.34

ClinPred

0.066

GERP RS

-2.0

PromoterAI

0.043

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.18

gMVP

0.28

Mutation Taster

=100/0

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

Publications

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11-65720321-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over