5-6600087-C-T

Position:

chr5-6600087-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017755.6(NSUN2):c.2143G>A(p.Val715Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00793 in 1,614,208 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0082 ( 64 hom. )

Consequence

NSUN2
NM_017755.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.188

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:

LINC01018 (HGNC:27394): (long intergenic non-protein coding RNA 1018)

LINC01018 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031422377).

BP6

Variant 5-6600087-C-T is Benign according to our data. Variant chr5-6600087-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 211757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-6600087-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00557 (849/152324) while in subpopulation NFE AF= 0.00966 (657/68030). AF 95% confidence interval is 0.00905. There are 4 homozygotes in gnomad4. There are 385 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSUN2	NM_017755.6 link	c.2143G>A	p.Val715Ile	missense_variant	19/19	ENST00000264670.11	NP_060225.4	Q08J23-1
NSUN2	NM_001193455.2 link	c.2038G>A	p.Val680Ile	missense_variant	18/18		NP_001180384.1	Q08J23-2
NSUN2	NR_037947.2 link	n.2123G>A		non_coding_transcript_exon_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSUN2	ENST00000264670.11 link	c.2143G>A	p.Val715Ile	missense_variant	19/19	1	NM_017755.6	ENSP00000264670.6		Q08J23-1

Frequencies

GnomAD3 genomes

AF:

0.00557

AC:

848

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00964

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00515

AC:

1295

AN:

251492

Hom.:

AF XY:

0.00534

AC XY:

726

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.00337

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000849

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00908

Gnomad OTH exome

AF:

0.00537

GnomAD4 exome

AF:

0.00817

AC:

11948

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00805

AC XY:

5854

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.00326

Gnomad4 ASJ exome

AF:

0.00386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00130

Gnomad4 FIN exome

AF:

0.00135

Gnomad4 NFE exome

AF:

0.00998

Gnomad4 OTH exome

AF:

0.00601

GnomAD4 genome

AF:

0.00557

AC:

849

AN:

152324

Hom.:

Cov.:

AF XY:

0.00517

AC XY:

385

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00204

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00966

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00871

Hom.:

Bravo

AF:

0.00584

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00506

AC:

614

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00862

EpiControl

AF:

0.00889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	NSUN2: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 17, 2016	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 06, 2017

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2018

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

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

1.0

DANN

Benign

0.50

DEOGEN2

Benign

0.058

T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.31

N;N

REVEL

Benign

0.011

Sift

Benign

0.28

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.094

B;.

Vest4

0.041

MVP

0.27

MPC

0.045

ClinPred

0.00060

GERP RS

0.24

Varity_R

0.017

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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