Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017755.6(NSUN2):c.2300G>A(p.Arg767Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00529 in 1,612,266 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0055 ( 27 hom. )

Consequence

NSUN2
NM_017755.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.770

Publications

4 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006454587).

BP6

Variant 5-6599930-C-T is Benign according to our data. Variant chr5-6599930-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211761.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00356 (542/152334) while in subpopulation NFE AF = 0.00594 (404/68026). AF 95% confidence interval is 0.00546. There are 2 homozygotes in GnomAd4. There are 248 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017755.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NSUN2	NM_017755.6	MANE Select	c.2300G>A	p.Arg767Gln	missense	Exon 19 of 19	NP_060225.4
NSUN2	NM_001193455.2		c.2195G>A	p.Arg732Gln	missense	Exon 18 of 18	NP_001180384.1
NSUN2	NR_037947.2		n.2280G>A		non_coding_transcript_exon	Exon 18 of 18

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NSUN2	ENST00000264670.11	TSL:1 MANE Select	c.2300G>A	p.Arg767Gln	missense	Exon 19 of 19	ENSP00000264670.6
NSUN2	ENST00000505892.5	TSL:1	n.2869G>A		non_coding_transcript_exon	Exon 13 of 13
NSUN2	ENST00000902915.1		c.2324G>A	p.Arg775Gln	missense	Exon 20 of 20	ENSP00000572974.1

Frequencies

GnomAD3 genomes

AF:

0.00357

AC:

543

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00594

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00357

AC:

895

AN:

250718

AF XY:

0.00382

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00277

Gnomad NFE exome

AF:

0.00559

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00547

AC:

7981

AN:

1459932

Hom.:

Cov.:

AF XY:

0.00537

AC XY:

3903

AN XY:

726202

show subpopulations

African (AFR)

AF:

0.000837

AC:

AN:

33434

American (AMR)

AF:

0.00179

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

26124

East Asian (EAS)

AF:

0.000126

AC:

AN:

39694

South Asian (SAS)

AF:

0.00314

AC:

271

AN:

86198

European-Finnish (FIN)

AF:

0.00392

AC:

207

AN:

52816

Middle Eastern (MID)

AF:

0.00238

AC:

AN:

5038

European-Non Finnish (NFE)

AF:

0.00630

AC:

6998

AN:

1111608

Other (OTH)

AF:

0.00527

AC:

318

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

439

878

1317

1756

2195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.00356

AC:

542

AN:

152334

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000962

AC:

AN:

41578

American (AMR)

AF:

0.00261

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00186

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00320

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00594

AC:

404

AN:

68026

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

121

151

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:

0.00473

Hom.:

Bravo

AF:

0.00343

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00348

AC:

422

EpiCase

AF:

0.00583

EpiControl

AF:

0.00664

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Inborn genetic diseases (1)

Intellectual disability, autosomal recessive 5 (1)

not specified (1)

NSUN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.60

M_CAP

Benign

0.0075

MetaRNN

Benign

0.0065

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

PhyloP100

0.77

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.44

REVEL

Benign

0.096

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.029

Vest4

0.14

MVP

0.18

MPC

0.066

ClinPred

0.047

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.066

gMVP

0.26

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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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over