rs1056148130

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_017755.6(NSUN2):c.1223G>A(p.Arg408Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R408R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NSUN2
NM_017755.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.33

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000263 (4/152154) while in subpopulation AMR AF= 0.000262 (4/15284). AF 95% confidence interval is 0.0000888. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NSUN2	NM_017755.6 linkuse as main transcript	c.1223G>A	p.Arg408Gln	missense_variant	11/19	ENST00000264670.11
NSUN2	NM_001193455.2 linkuse as main transcript	c.1118G>A	p.Arg373Gln	missense_variant	10/18
NSUN2	NR_037947.2 linkuse as main transcript	n.1203G>A		non_coding_transcript_exon_variant	10/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSUN2	ENST00000264670.11 linkuse as main transcript	c.1223G>A	p.Arg408Gln	missense_variant	11/19	1	NM_017755.6	P2	Q08J23-1
NSUN2	ENST00000505892.5 linkuse as main transcript	n.1792G>A		non_coding_transcript_exon_variant	5/13	1
NSUN2	ENST00000506139.5 linkuse as main transcript	c.1118G>A	p.Arg373Gln	missense_variant	10/18	2		A2	Q08J23-2
NSUN2	ENST00000504374.5 linkuse as main transcript	c.*529G>A		3_prime_UTR_variant, NMD_transcript_variant	10/18	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251198

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 17, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Uncertain

0.050

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Benign

-0.73

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.080

T;T

Polyphen

0.94

P;.

Vest4

0.77

MutPred

0.41

Loss of helix (P = 0.0068);.;

MVP

0.75

MPC

0.33

ClinPred

0.89

GERP RS

5.6

Varity_R

0.28

gMVP

0.70

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over