Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_017755.6(NSUN2):c.915C>T(p.Arg305Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000837 in 1,613,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

NSUN2
NM_017755.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -2.63

Publications

0 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 5-6616833-G-A is Benign according to our data. Variant chr5-6616833-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211762.

BP7

Synonymous conserved (PhyloP=-2.63 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00019 (29/152248) while in subpopulation AFR AF = 0.000265 (11/41540). AF 95% confidence interval is 0.000148. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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
NSUN2	NM_017755.6	MANE Select	c.915C>T	p.Arg305Arg	synonymous	Exon 9 of 19	NP_060225.4
NSUN2	NM_001193455.2		c.810C>T	p.Arg270Arg	synonymous	Exon 8 of 18	NP_001180384.1
NSUN2	NR_037947.2		n.895C>T		non_coding_transcript_exon	Exon 8 of 18

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NSUN2	ENST00000264670.11	TSL:1 MANE Select	c.915C>T	p.Arg305Arg	synonymous	Exon 9 of 19	ENSP00000264670.6
NSUN2	ENST00000505892.5	TSL:1	n.1484C>T		non_coding_transcript_exon	Exon 3 of 13
NSUN2	ENST00000506139.5	TSL:2	c.810C>T	p.Arg270Arg	synonymous	Exon 8 of 18	ENSP00000420957.1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.0110

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000518

AC:

AN:

250992

AF XY:

0.0000664

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000725

AC:

106

AN:

1461254

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

726922

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33464

American (AMR)

AF:

0.000157

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1111670

Other (OTH)

AF:

0.000215

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.000190

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41540

American (AMR)

AF:

0.000262

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.0000965

Hom.:

Bravo

AF:

0.000268

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

not specified (1)

NSUN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.95

(source)

DANN

Benign

0.42

PhyloP100

-2.6

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Mutation Taster

=100/0

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.

rs527650370

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over