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):

syndromic intellectual disability
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, autosomal recessive 5
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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

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	UniProt
NSUN2	NM_017755.6	MANE Select	c.529C>T	p.His177Tyr	missense	Exon 5 of 19	NP_060225.4
NSUN2	NM_001193455.2		c.424C>T	p.His142Tyr	missense	Exon 4 of 18	NP_001180384.1	Q08J23-2
NSUN2	NR_037947.2		n.594C>T		non_coding_transcript_exon	Exon 5 of 18

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NSUN2	ENST00000264670.11	TSL:1 MANE Select	c.529C>T	p.His177Tyr	missense	Exon 5 of 19	ENSP00000264670.6	Q08J23-1
NSUN2	ENST00000902915.1		c.529C>T	p.His177Tyr	missense	Exon 5 of 20	ENSP00000572974.1
NSUN2	ENST00000939214.1		c.529C>T	p.His177Tyr	missense	Exon 5 of 19	ENSP00000609273.1

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal recessive 5 (3)

not provided (3)

Inborn genetic diseases (1)

Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0089

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.1

PhyloP100

7.4

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.24

Sift

Benign

0.079

Sift4G

Uncertain

0.056

Polyphen

0.96

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

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

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

Computational scores

Splicing

Publications

Other links and lift over