rs149196615

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_017755.6(NSUN2):c.529C>T(p.His177Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00061 in 1,604,466 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00063 ( 2 hom. )

Consequence

NSUN2
NM_017755.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7

Conservation

PhyloP100: 7.38

Publications

7 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15167111).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000449 (68/151304) while in subpopulation AMR AF = 0.00132 (20/15186). AF 95% confidence interval is 0.000872. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSUN2	NM_017755.6 link	c.529C>T	p.His177Tyr	missense_variant	Exon 5 of 19	ENST00000264670.11	NP_060225.4	Q08J23-1
NSUN2	NM_001193455.2 link	c.424C>T	p.His142Tyr	missense_variant	Exon 4 of 18		NP_001180384.1	Q08J23-2
NSUN2	NR_037947.2 link	n.594C>T		non_coding_transcript_exon_variant	Exon 5 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NSUN2	ENST00000264670.11 link	c.529C>T	p.His177Tyr	missense_variant	Exon 5 of 19	1	NM_017755.6	ENSP00000264670.6	Q08J23-1
NSUN2	ENST00000506139.5 link	c.424C>T	p.His142Tyr	missense_variant	Exon 4 of 18	2		ENSP00000420957.1	Q08J23-2
NSUN2	ENST00000504374.5 link	n.529C>T		non_coding_transcript_exon_variant	Exon 5 of 18	2		ENSP00000421783.1	A0A140T9Y7
NSUN2	ENST00000505264.1 link	n.139C>T		non_coding_transcript_exon_variant	Exon 2 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.000456

AC:

AN:

151188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00132

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000501

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000516

AC:

126

AN:

244390

AF XY:

0.000591

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000612

Gnomad ASJ exome

AF:

0.00202

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000589

Gnomad OTH exome

AF:

0.000667

GnomAD4 exome

AF:

0.000627

AC:

911

AN:

1453162

Hom.:

Cov.:

AF XY:

0.000624

AC XY:

451

AN XY:

722656

show subpopulations

African (AFR)

AF:

0.0000609

AC:

AN:

32850

American (AMR)

AF:

0.000702

AC:

AN:

42706

Ashkenazi Jewish (ASJ)

AF:

0.00193

AC:

AN:

25954

East Asian (EAS)

AF:

0.00

AC:

AN:

39600

South Asian (SAS)

AF:

0.000814

AC:

AN:

83586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.000360

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

0.000645

AC:

716

AN:

1109608

Other (OTH)

AF:

0.000716

AC:

AN:

60020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<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:

0.000449

AC:

AN:

151304

Hom.:

Cov.:

AF XY:

0.000501

AC XY:

AN XY:

73868

show subpopulations

African (AFR)

AF:

0.0000971

AC:

AN:

41188

American (AMR)

AF:

0.00132

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00104

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000501

AC:

AN:

67922

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000720

Hom.:

Bravo

AF:

0.000650

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000469

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 5

Pathogenic:1Uncertain:2

Nov 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Uncertain:3

Feb 13, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 177 of the NSUN2 protein (p.His177Tyr). This variant is present in population databases (rs149196615, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NSUN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 129843). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 28, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with Dubowitz syndrome who was also heterozygous for another variant in NSUN2 (Dyment DA et al., 2021); This variant is associated with the following publications: (PMID: 33098347) -

Inborn genetic diseases

Uncertain:1

Jan 08, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.529C>T (p.H177Y) alteration is located in exon 5 (coding exon 5) of the NSUN2 gene. This alteration results from a C to T substitution at nucleotide position 529, causing the histidine (H) at amino acid position 177 to be replaced by a tyrosine (Y). The p.H177Y alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.0089

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

7.4

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.24

Sift

Benign

0.079

T;T

Sift4G

Uncertain

0.056

T;T

Polyphen

0.96

D;.

Vest4

0.65

MVP

0.45

MPC

1.3

ClinPred

0.48

GERP RS

5.3

Varity_R

0.64

gMVP

0.63

Mutation Taster

=252/48

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over