5-6599909-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_017755.6(NSUN2):c.*17G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000304 in 1,606,680 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: NSUN2 NM_017755.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.405

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-6599909-C-T is Benign according to our data. Variant chr5-6599909-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 354046.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00153 (233/152336) while in subpopulation AFR AF= 0.005 (208/41566). AF 95% confidence interval is 0.00445. There are 1 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSUN2	NM_017755.6	c.*17G>A		3_prime_UTR_variant	19/19	ENST00000264670.11
NSUN2	NM_001193455.2	c.*17G>A		3_prime_UTR_variant	18/18
NSUN2	NR_037947.2	n.2301G>A		non_coding_transcript_exon_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSUN2	ENST00000264670.11	c.*17G>A		3_prime_UTR_variant	19/19	1	NM_017755.6	P2
LINC01018	ENST00000661215.1	n.757-212C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000486 AC: 121 AN: 248898 Hom.: 0 AF XY: 0.000401 AC XY: 54 AN XY: 134570

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000975

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000175 AC: 255 AN: 1454344 Hom.: 0 Cov.: 31 AF XY: 0.000165 AC XY: 119 AN XY: 722882

Gnomad4 AFR exome AF: 0.00417

Gnomad4 AMR exome AF: 0.000538

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000874

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000416

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74496

Gnomad4 AFR AF: 0.00500

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000726 Hom.: 0

Bravo AF: 0.00159

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal recessive 5 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.1
Dann	Benign	0.49

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: rs201903423; hg19: chr5-6600022;