dbSNP rs140003855: NSUN2:p.Gly255Ser (chr5-6620158-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_017755.6(NSUN2):c.763G>A(p.Gly255Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0001 in 1,610,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NSUN2
NM_017755.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.65

Publications

5 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: Uncertain_significance. The variant received 0 ACMG points.

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.763G>A	p.Gly255Ser	missense	Exon 7 of 19	NP_060225.4
NSUN2	NM_001193455.2		c.658G>A	p.Gly220Ser	missense	Exon 6 of 18	NP_001180384.1	Q08J23-2
NSUN2	NR_037947.2		n.743G>A		non_coding_transcript_exon	Exon 6 of 18

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NSUN2	ENST00000264670.11	TSL:1 MANE Select	c.763G>A	p.Gly255Ser	missense	Exon 7 of 19	ENSP00000264670.6	Q08J23-1
NSUN2	ENST00000505892.5	TSL:1	n.1332G>A		non_coding_transcript_exon	Exon 1 of 13
NSUN2	ENST00000902915.1		c.763G>A	p.Gly255Ser	missense	Exon 7 of 20	ENSP00000572974.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000486

AC:

AN:

246900

AF XY:

0.0000524

show subpopulations

Gnomad AFR exome

AF:

0.0000627

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

157

AN:

1457956

Hom.:

Cov.:

AF XY:

0.0000965

AC XY:

AN XY:

725290

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33218

American (AMR)

AF:

0.00

AC:

AN:

44016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39352

South Asian (SAS)

AF:

0.00

AC:

AN:

85618

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000134

AC:

149

AN:

1110384

Other (OTH)

AF:

0.0000996

AC:

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

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:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.613

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:

0.0000801

Hom.:

Bravo

AF:

0.0000416

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 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

PhyloP100

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.29

gMVP

0.57

Mutation Taster

=19/81

disease causing

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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