NM_017755.6:c.2143G>T

Variant names:

• chr5-6600087-C-A
• NM_017755.6:c.2143G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017755.6(NSUN2):​c.2143G>T​(p.Val715Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V715I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NSUN2 NM_017755.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.188

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07032102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSUN2	NM_017755.6	c.2143G>T	p.Val715Phe	missense_variant	Exon 19 of 19	ENST00000264670.11	NP_060225.4
NSUN2	NM_001193455.2	c.2038G>T	p.Val680Phe	missense_variant	Exon 18 of 18		NP_001180384.1
NSUN2	NR_037947.2	n.2123G>T		non_coding_transcript_exon_variant	Exon 18 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSUN2	ENST00000264670.11	c.2143G>T	p.Val715Phe	missense_variant	Exon 19 of 19	1	NM_017755.6	ENSP00000264670.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with NSUN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 715 of the NSUN2 protein (p.Val715Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.7
DANN	Benign	0.76
DEOGEN2	Benign	0.055	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.065
Sift	Benign	0.17	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.64	P;.
Vest4		0.12
MutPred		0.27		Loss of ubiquitination at K711 (P = 0.1016);.;
MVP		0.33
MPC		0.097
ClinPred		0.12	T
GERP RS		0.24
Varity_R		0.036
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-6600200;