rs138716662

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_017755.6(NSUN2):c.222C>T(p.Leu74Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,184 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 9 hom. )

Consequence

NSUN2
NM_017755.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.205

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 links:

NSUN2 (HGNC:):

NSUN2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 5-6632631-G-A is Benign according to our data. Variant chr5-6632631-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-6632631-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.205 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00154 (234/152320) while in subpopulation NFE AF= 0.00275 (187/68038). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSUN2	NM_017755.6 linkuse as main transcript	c.222C>T	p.Leu74Leu	synonymous_variant	2/19	ENST00000264670.11	NP_060225.4	Q08J23-1
NSUN2	NM_001193455.2 linkuse as main transcript	c.222C>T	p.Leu74Leu	synonymous_variant	2/18		NP_001180384.1	Q08J23-2
NSUN2	NR_037947.2 linkuse as main transcript	n.287C>T		non_coding_transcript_exon_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NSUN2	ENST00000264670.11 linkuse as main transcript	c.222C>T	p.Leu74Leu	synonymous_variant	2/19	1	NM_017755.6	ENSP00000264670.6	Q08J23-1
NSUN2	ENST00000506139.5 linkuse as main transcript	c.222C>T	p.Leu74Leu	synonymous_variant	2/18	2		ENSP00000420957.1	Q08J23-2
NSUN2	ENST00000504374.5 linkuse as main transcript	n.222C>T		non_coding_transcript_exon_variant	2/18	2		ENSP00000421783.1	A0A140T9Y7

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

234

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00275

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00195

AC:

489

AN:

251316

Hom.:

AF XY:

0.00209

AC XY:

284

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00351

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00256

AC:

3740

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

1824

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.00215

Gnomad4 NFE exome

AF:

0.00306

Gnomad4 OTH exome

AF:

0.00235

GnomAD4 genome

AF:

0.00154

AC:

234

AN:

152320

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00275

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00254

Hom.:

Bravo

AF:

0.00158

EpiCase

AF:

0.00278

EpiControl

AF:

0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NSUN2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2020	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 03, 2017

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability, autosomal recessive 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over