rs587776908

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_017755.6(NSUN2):c.2035G>A(p.Gly679Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G679G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NSUN2
NM_017755.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.92

Publications

14 publications found

Variant links:

Genes affected

NSUN2 (HGNC:25994): (NOP2/Sun RNA methyltransferase 2) This gene encodes a methyltransferase that catalyzes the methylation of cytosine to 5-methylcytosine (m5C) at position 34 of intron-containing tRNA(Leu)(CAA) precursors. This modification is necessary to stabilize the anticodon-codon pairing and correctly translate the mRNA. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Mar 2011]

NSUN2 links:

LINC01018 (HGNC:27394): (long intergenic non-protein coding RNA 1018)

LINC01018 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 5-6600195-C-T is Pathogenic according to our data. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-6600195-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 31678.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSUN2	NM_017755.6 link	c.2035G>A	p.Gly679Arg	missense_variant	Exon 19 of 19	ENST00000264670.11	NP_060225.4	Q08J23-1
NSUN2	NM_001193455.2 link	c.1930G>A	p.Gly644Arg	missense_variant	Exon 18 of 18		NP_001180384.1	Q08J23-2
NSUN2	NR_037947.2 link	n.2015G>A		non_coding_transcript_exon_variant	Exon 18 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSUN2	ENST00000264670.11 link	c.2035G>A	p.Gly679Arg	missense_variant	Exon 19 of 19	1	NM_017755.6	ENSP00000264670.6		Q08J23-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251422

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111998

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 5

Pathogenic:1

May 04, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Jul 14, 2020

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect due to failure of the protein to localize to the nucleoli in most transfected cells as compared to wild-type (Khan et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28397838, 22541562) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

D;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.045

MutationAssessor

Pathogenic

3.2

M;.

PhyloP100

6.9

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-7.3

D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.85

Gain of MoRF binding (P = 0.0253);.;

MVP

0.86

MPC

0.37

ClinPred

0.97

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.80

gMVP

0.92

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over