5-6599930-C-T

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. 15/23 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

2
1
16

Clinical Significance

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

Conservation

PhyloP100: 0.770
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]
LINC01018 (HGNC:27394): (long intergenic non-protein coding RNA 1018)

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 id is 211761.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6}. Variant chr5-6599930-C-T is described in Lovd as [Likely_benign].
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 FAILED quality control check.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NSUN2NM_017755.6 linkc.2300G>A p.Arg767Gln missense_variant Exon 19 of 19 ENST00000264670.11 NP_060225.4 Q08J23-1
NSUN2NM_001193455.2 linkc.2195G>A p.Arg732Gln missense_variant Exon 18 of 18 NP_001180384.1 Q08J23-2
NSUN2NR_037947.2 linkn.2280G>A non_coding_transcript_exon_variant Exon 18 of 18

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NSUN2ENST00000264670.11 linkc.2300G>A p.Arg767Gln missense_variant Exon 19 of 19 1 NM_017755.6 ENSP00000264670.6 Q08J23-1

Frequencies

GnomAD3 genomes
AF:
0.00357
AC:
543
AN:
152216
Hom.:
2
Cov.:
33
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.:
27
Cov.:
31
AF XY:
0.00537
AC XY:
3903
AN XY:
726202
show subpopulations
Gnomad4 AFR exome
AF:
0.000837
AC:
28
AN:
33434
Gnomad4 AMR exome
AF:
0.00179
AC:
80
AN:
44720
Gnomad4 ASJ exome
AF:
0.00237
AC:
62
AN:
26124
Gnomad4 EAS exome
AF:
0.000126
AC:
5
AN:
39694
Gnomad4 SAS exome
AF:
0.00314
AC:
271
AN:
86198
Gnomad4 FIN exome
AF:
0.00392
AC:
207
AN:
52816
Gnomad4 NFE exome
AF:
0.00630
AC:
6998
AN:
1111608
Gnomad4 Remaining exome
AF:
0.00527
AC:
318
AN:
60300
Heterozygous variant carriers
0
439
878
1317
1756
2195
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
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.:
2
Cov.:
33
AF XY:
0.00333
AC XY:
248
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000962
AC:
0.000962047
AN:
0.000962047
Gnomad4 AMR
AF:
0.00261
AC:
0.00261301
AN:
0.00261301
Gnomad4 ASJ
AF:
0.00202
AC:
0.00201845
AN:
0.00201845
Gnomad4 EAS
AF:
0.000193
AC:
0.00019305
AN:
0.00019305
Gnomad4 SAS
AF:
0.00186
AC:
0.00186258
AN:
0.00186258
Gnomad4 FIN
AF:
0.00320
AC:
0.00320151
AN:
0.00320151
Gnomad4 NFE
AF:
0.00594
AC:
0.00593891
AN:
0.00593891
Gnomad4 OTH
AF:
0.00331
AC:
0.00330813
AN:
0.00330813
Heterozygous variant carriers
0
30
60
91
121
151
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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.:
1
Bravo
AF:
0.00343
TwinsUK
AF:
0.00378
AC:
14
ALSPAC
AF:
0.00441
AC:
17
ESP6500AA
AF:
0.00113
AC:
5
ESP6500EA
AF:
0.00581
AC:
50
ExAC
AF:
0.00348
AC:
422
EpiCase
AF:
0.00583
EpiControl
AF:
0.00664

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:4
Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

NSUN2: BP4, BS2 -

Dec 13, 2023
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 27, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Uncertain:1
Dec 07, 2018
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R767Q variant (also known as c.2300G>A), located in coding exon 19 of the NSUN2 gene, results from a G to A substitution at nucleotide position 2300. The arginine at codon 767 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not specified Benign:1
Jul 22, 2015
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

NSUN2-related disorder Benign:1
Mar 31, 2020
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability, autosomal recessive 5 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Benign
0.042
T;.
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.39
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.60
T;T
M_CAP
Benign
0.0075
T
MetaRNN
Benign
0.0065
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
N;.
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.44
N;N
REVEL
Benign
0.096
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.029
B;.
Vest4
0.14
MVP
0.18
MPC
0.066
ClinPred
0.047
T
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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs140673211; hg19: chr5-6600043; COSMIC: COSV52957471; COSMIC: COSV52957471; API