Genetic Variant NSUN2:c.359+2056C>T (chr5-6629817-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017755.6(NSUN2):c.359+2056C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 151,962 control chromosomes in the GnomAD database, including 9,025 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.34 ( 9025 hom., cov: 32)

Consequence

NSUN2
NM_017755.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.365

Publications

13 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
NSUN2	NM_017755.6	MANE Select	c.359+2056C>T	intron	N/A	NP_060225.4
NSUN2	NM_001193455.2		c.254+2782C>T	intron	N/A	NP_001180384.1	Q08J23-2
NSUN2	NR_037947.2		n.424+2056C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NSUN2	ENST00000264670.11	TSL:1 MANE Select	c.359+2056C>T	intron	N/A	ENSP00000264670.6	Q08J23-1
NSUN2	ENST00000902915.1		c.359+2056C>T	intron	N/A	ENSP00000572974.1
NSUN2	ENST00000939214.1		c.359+2056C>T	intron	N/A	ENSP00000609273.1

Frequencies

GnomAD3 genomes

AF:

0.339

AC:

51448

AN:

151842

Hom.:

9022

Cov.:

show subpopulations

Gnomad AFR

AF:

0.294

Gnomad AMI

AF:

0.511

Gnomad AMR

AF:

0.421

Gnomad ASJ

AF:

0.323

Gnomad EAS

AF:

0.261

Gnomad SAS

AF:

0.281

Gnomad FIN

AF:

0.448

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.340

Gnomad OTH

AF:

0.329

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.339

AC:

51475

AN:

151962

Hom.:

9025

Cov.:

AF XY:

0.343

AC XY:

25461

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.294

AC:

12179

AN:

41450

American (AMR)

AF:

0.421

AC:

6424

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

1117

AN:

3462

East Asian (EAS)

AF:

0.261

AC:

1345

AN:

5154

South Asian (SAS)

AF:

0.281

AC:

1354

AN:

4812

European-Finnish (FIN)

AF:

0.448

AC:

4726

AN:

10552

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.340

AC:

23099

AN:

67956

Other (OTH)

AF:

0.325

AC:

684

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1689

3379

5068

6758

8447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

496

992

1488

1984

2480

<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:

0.339

Hom.:

37167

Bravo

AF:

0.337

Asia WGS

AF:

0.318

AC:

1106

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.8

(source)

DANN

Benign

0.52

PhyloP100

0.36

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over