Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000264670.11(NSUN2):c.1010A>G(p.Glu337Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000763 in 1,442,446 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E337E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000076 ( 1 hom. )

Consequence

NSUN2
ENST00000264670.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.10

Publications

0 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 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 5
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Dubowitz syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
RASopathy
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

NSUN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000264670.11. 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.1010A>G	p.Glu337Gly	missense	Exon 9 of 19	NP_060225.4
NSUN2	NM_001193455.2		c.905A>G	p.Glu302Gly	missense	Exon 8 of 18	NP_001180384.1
NSUN2	NR_037947.2		n.990A>G		non_coding_transcript_exon	Exon 8 of 18

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NSUN2	ENST00000264670.11	TSL:1 MANE Select	c.1010A>G	p.Glu337Gly	missense	Exon 9 of 19	ENSP00000264670.6
NSUN2	ENST00000505892.5	TSL:1	n.1579A>G		non_coding_transcript_exon	Exon 3 of 13
NSUN2	ENST00000506139.5	TSL:2	c.905A>G	p.Glu302Gly	missense	Exon 8 of 18	ENSP00000420957.1

Frequencies

GnomAD3 genomes

AF:

0.000104

AC:

AN:

38596

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000239

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000414

AC:

AN:

241560

AF XY:

0.0000382

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:

0.0000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000755

AC:

106

AN:

1403850

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

698224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31530

American (AMR)

AF:

0.00

AC:

AN:

42156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23994

East Asian (EAS)

AF:

0.00

AC:

AN:

36572

South Asian (SAS)

AF:

0.00

AC:

AN:

80998

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5478

European-Non Finnish (NFE)

AF:

0.0000958

AC:

103

AN:

1074980

Other (OTH)

AF:

0.0000527

AC:

AN:

56928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

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

AF:

0.000104

AC:

AN:

38596

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

19774

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

9110

American (AMR)

AF:

0.00

AC:

AN:

4576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

720

East Asian (EAS)

AF:

0.00

AC:

AN:

1362

South Asian (SAS)

AF:

0.00

AC:

AN:

1310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000239

AC:

AN:

16748

Other (OTH)

AF:

0.00

AC:

AN:

510

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00955443), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0062

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

PhyloP100

7.1

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.19

Sift

Benign

0.20

Sift4G

Benign

0.33

Polyphen

0.27

Vest4

0.65

MutPred

0.45

Loss of stability (P = 0.0338)

MVP

0.49

MPC

0.21

ClinPred

0.59

GERP RS

5.6

Varity_R

0.25

gMVP

0.58

Mutation Taster

=65/35

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs758250936

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