rs899944658

Positions:

• chr5-6607258-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000264670.11(NSUN2):​c.1450A>G​(p.Ile484Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,892 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (1 hom.)
• Consequence: NSUN2 ENST00000264670.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.71

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039351612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSUN2	NM_017755.6	c.1450A>G	p.Ile484Val	missense_variant	13/19	ENST00000264670.11	NP_060225.4
NSUN2	NM_001193455.2	c.1345A>G	p.Ile449Val	missense_variant	12/18		NP_001180384.1
NSUN2	NR_037947.2	n.1430A>G		non_coding_transcript_exon_variant	12/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSUN2	ENST00000264670.11	c.1450A>G	p.Ile484Val	missense_variant	13/19	1	NM_017755.6	ENSP00000264670	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461892 Hom.: 1 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.022
DANN	Benign	0.66
DEOGEN2	Benign	0.032	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.060
Sift	Benign	0.42	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0	B;.
Vest4		0.052
MutPred		0.20		Loss of catalytic residue at I484 (P = 0.0412);.;
MVP		0.18
MPC		0.046
ClinPred		0.048	T
GERP RS		-9.4
Varity_R		0.018
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs899944658; hg19: chr5-6607371;