5-6599930-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017755.6(NSUN2):c.2300G>A(p.Arg767Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00529 in 1,612,266 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (27 hom.)
• Consequence: NSUN2 NM_017755.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.770

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]

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

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006454587).
• BP6: Variant 5-6599930-C-T is Benign according to our data. Variant chr5-6599930-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211761.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1}. Variant chr5-6599930-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00356 (542/152334) while in subpopulation NFE AF= 0.00594 (404/68026). AF 95% confidence interval is 0.00546. There are 2 homozygotes in gnomad4. There are 248 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSUN2	NM_017755.6	c.2300G>A	p.Arg767Gln	missense_variant	19/19	ENST00000264670.11
NSUN2	NM_001193455.2	c.2195G>A	p.Arg732Gln	missense_variant	18/18
NSUN2	NR_037947.2	n.2280G>A		non_coding_transcript_exon_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSUN2	ENST00000264670.11	c.2300G>A	p.Arg767Gln	missense_variant	19/19	1	NM_017755.6	P2
LINC01018	ENST00000661215.1	n.757-191C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 543 AN: 152216 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00594

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00357 AC: 895 AN: 250718 Hom.: 1 AF XY: 0.00382 AC XY: 518 AN XY: 135540

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00307

Gnomad FIN exome AF: 0.00277

Gnomad NFE exome AF: 0.00559

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00547 AC: 7981 AN: 1459932 Hom.: 27 Cov.: 31 AF XY: 0.00537 AC XY: 3903 AN XY: 726202

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00314

Gnomad4 FIN exome AF: 0.00392

Gnomad4 NFE exome AF: 0.00630

Gnomad4 OTH exome AF: 0.00527

GnomAD4 genome AF: 0.00356 AC: 542 AN: 152334 Hom.: 2 Cov.: 33 AF XY: 0.00333 AC XY: 248 AN XY: 74480

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.00594

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00490 Hom.: 1

Bravo AF: 0.00343

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00348 AC: 422

EpiCase AF: 0.00583

EpiControl AF: 0.00664

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 27, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NSUN2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2022	See Variant Classification Assertion Criteria. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2018

The p.R767Q variant (also known as c.2300G>A), located in coding exon 19 of the NSUN2 gene, results from a G to A substitution at nucleotide position 2300. The arginine at codon 767 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 22, 2015

- -

NSUN2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 31, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability, autosomal recessive 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	0.099
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.042	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.0065	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.096
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.029	B;.
Vest4		0.14
MVP		0.18
MPC		0.066
ClinPred		0.047	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.26

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

Other links and lift over

dbSNP: rs140673211; hg19: chr5-6600043; COSMIC: COSV52957471; COSMIC: COSV52957471;