NM_017755.6:c.1998-8A>G

Variant names:

• chr5-6600240-T-C
• rs797045836
• NM_017755.6:c.1998-8A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017755.6(NSUN2):​c.1998-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NSUN2 NM_017755.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002186
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.85
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSUN2	NM_017755.6	c.1998-8A>G		splice_region_variant, intron_variant	Intron 18 of 18	ENST00000264670.11	NP_060225.4
NSUN2	NM_001193455.2	c.1893-8A>G		splice_region_variant, intron_variant	Intron 17 of 17		NP_001180384.1
NSUN2	NR_037947.2	n.1978-8A>G		splice_region_variant, intron_variant	Intron 17 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSUN2	ENST00000264670.11	c.1998-8A>G		splice_region_variant, intron_variant	Intron 18 of 18	1	NM_017755.6	ENSP00000264670.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456958 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724134

African (AFR) AF: 0.00 AC: 0 AN: 33272

American (AMR) AF: 0.00 AC: 0 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 85976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108542

Other (OTH) AF: 0.00 AC: 0 AN: 60182

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 22, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.26
DANN	Benign	0.37
PhyloP100		-2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0060
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

Other links and lift over

dbSNP: rs797045836; hg19: chr5-6600353;