5-6599876-A-C

Position:

• chr5-6599876-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017755.6(NSUN2):​c.*50T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,551,342 control chromosomes in the GnomAD database, including 338 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (26 hom., cov: 33)
  • Exomes 𝑓: 0.019 (312 hom.)
• Consequence: NSUN2 NM_017755.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.289

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-6599876-A-C is Benign according to our data. Variant chr5-6599876-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 354044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2015/152334) while in subpopulation NFE AF= 0.0212 (1441/68020). AF 95% confidence interval is 0.0203. There are 26 homozygotes in gnomad4. There are 924 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSUN2	NM_017755.6	c.*50T>G		3_prime_UTR_variant	19/19	ENST00000264670.11
NSUN2	NM_001193455.2	c.*50T>G		3_prime_UTR_variant	18/18
NSUN2	NR_037947.2	n.2334T>G		non_coding_transcript_exon_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSUN2	ENST00000264670.11	c.*50T>G		3_prime_UTR_variant	19/19	1	NM_017755.6	P2
LINC01018	ENST00000661215.1	n.757-245A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2017 AN: 152216 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00475

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0129 AC: 3009 AN: 233670 Hom.: 35 AF XY: 0.0131 AC XY: 1654 AN XY: 126104

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.00361

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.00514

Gnomad FIN exome AF: 0.00244

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.0190 AC: 26516 AN: 1399008 Hom.: 312 Cov.: 25 AF XY: 0.0186 AC XY: 12930 AN XY: 695556

Gnomad4 AFR exome AF: 0.00280

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.00334

Gnomad4 EAS exome AF: 0.0000763

Gnomad4 SAS exome AF: 0.00442

Gnomad4 FIN exome AF: 0.00419

Gnomad4 NFE exome AF: 0.0228

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0132 AC: 2015 AN: 152334 Hom.: 26 Cov.: 33 AF XY: 0.0124 AC XY: 924 AN XY: 74484

Gnomad4 AFR AF: 0.00474

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.0212

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00634 Hom.: 3

Bravo AF: 0.0147

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal recessive 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.0
DANN	Benign	0.34

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

LitVar

Other links and lift over

dbSNP: rs56282400; hg19: chr5-6599989;