rs202085420

Positions:

• chr5-6610951-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BS1_Supporting

The NM_017755.6(NSUN2):​c.1226+4A>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: NSUN2 NM_017755.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9817
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.166

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000427 (65/152212) while in subpopulation AFR AF= 0.00128 (53/41538). AF 95% confidence interval is 0.001. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSUN2	NM_017755.6	c.1226+4A>T		splice_donor_region_variant, intron_variant		ENST00000264670.11	NP_060225.4
NSUN2	NM_001193455.2	c.1121+4A>T		splice_donor_region_variant, intron_variant			NP_001180384.1
NSUN2	NR_037947.2	n.1206+4A>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSUN2	ENST00000264670.11	c.1226+4A>T		splice_donor_region_variant, intron_variant		1	NM_017755.6	ENSP00000264670	P2
NSUN2	ENST00000505892.5	n.1795+4A>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		1
NSUN2	ENST00000506139.5	c.1121+4A>T		splice_donor_region_variant, intron_variant		2		ENSP00000420957	A2
NSUN2	ENST00000504374.5	c.*532+4A>T		splice_donor_region_variant, intron_variant, NMD_transcript_variant		2		ENSP00000421783

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152094 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 251136 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135764

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000187 AC: 274 AN: 1461750 Hom.: 0 Cov.: 30 AF XY: 0.000186 AC XY: 135 AN XY: 727176

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152212 Hom.: 0 Cov.: 31 AF XY: 0.000363 AC XY: 27 AN XY: 74418

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.000536

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	This sequence change falls in intron 11 of the NSUN2 gene. It does not directly change the encoded amino acid sequence of the NSUN2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs202085420, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with NSUN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 436075). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2023	In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 05, 2015

- -

Intellectual disability, autosomal recessive 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.4
DANN	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.62		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202085420; hg19: chr5-6611064;