NM_017755.6:c.537+8A>G

Variant names:

• chr5-6623206-T-C
• rs149276590
• NM_017755.6:c.537+8A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_017755.6(NSUN2):​c.537+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 0.000373 in 1,592,304 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: NSUN2 NM_017755.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002784
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.148

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 Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-6623206-T-C is Benign according to our data. Variant chr5-6623206-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 436082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00181 (274/151788) while in subpopulation AFR AF= 0.00628 (260/41394). AF 95% confidence interval is 0.00565. There are 0 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSUN2	NM_017755.6	c.537+8A>G		splice_region_variant, intron_variant	Intron 5 of 18	ENST00000264670.11	NP_060225.4
NSUN2	NM_001193455.2	c.432+8A>G		splice_region_variant, intron_variant	Intron 4 of 17		NP_001180384.1
NSUN2	NR_037947.2	n.602+8A>G		splice_region_variant, intron_variant	Intron 5 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSUN2	ENST00000264670.11	c.537+8A>G		splice_region_variant, intron_variant	Intron 5 of 18	1	NM_017755.6	ENSP00000264670.6
NSUN2	ENST00000506139.5	c.432+8A>G		splice_region_variant, intron_variant	Intron 4 of 17	2		ENSP00000420957.1
NSUN2	ENST00000504374.5	n.537+8A>G		splice_region_variant, intron_variant	Intron 5 of 17	2		ENSP00000421783.1
NSUN2	ENST00000505264.1	n.147+8A>G		splice_region_variant, intron_variant	Intron 2 of 3	4

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 275 AN: 151670 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000526

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000450 AC: 105 AN: 233114 Hom.: 1 AF XY: 0.000372 AC XY: 47 AN XY: 126212

Gnomad AFR exome AF: 0.00620

Gnomad AMR exome AF: 0.000103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000388

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000353

GnomAD4 exome AF: 0.000222 AC: 320 AN: 1440516 Hom.: 1 Cov.: 31 AF XY: 0.000187 AC XY: 134 AN XY: 716204

Gnomad4 AFR exome AF: 0.00831

Gnomad4 AMR exome AF: 0.000182

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000621

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.000588

GnomAD4 genome AF: 0.00181 AC: 274 AN: 151788 Hom.: 0 Cov.: 30 AF XY: 0.00186 AC XY: 138 AN XY: 74176

Gnomad4 AFR AF: 0.00628

Gnomad4 AMR AF: 0.000460

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000928 Hom.: 2

Bravo AF: 0.00218

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 19, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.98
DANN	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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: rs149276590; hg19: chr5-6623319;