rs138716662

Variant names:

• chr5-6632631-G-A
• rs138716662
• NM_017755.6:c.222C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-6632631-G-A
• chr5-6632631-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_017755.6(NSUN2):​c.222C>T​(p.Leu74Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,184 control chromosomes in the GnomAD database, including 9 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 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: NSUN2 NM_017755.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.205

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-6632631-G-A is Benign according to our data. Variant chr5-6632631-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-6632631-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.205 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00154 (234/152320) while in subpopulation NFE AF= 0.00275 (187/68038). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSUN2	NM_017755.6	c.222C>T	p.Leu74Leu	synonymous_variant	Exon 2 of 19	ENST00000264670.11	NP_060225.4
NSUN2	NM_001193455.2	c.222C>T	p.Leu74Leu	synonymous_variant	Exon 2 of 18		NP_001180384.1
NSUN2	NR_037947.2	n.287C>T		non_coding_transcript_exon_variant	Exon 2 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSUN2	ENST00000264670.11	c.222C>T	p.Leu74Leu	synonymous_variant	Exon 2 of 19	1	NM_017755.6	ENSP00000264670.6
NSUN2	ENST00000506139.5	c.222C>T	p.Leu74Leu	synonymous_variant	Exon 2 of 18	2		ENSP00000420957.1
NSUN2	ENST00000504374.5	n.222C>T		non_coding_transcript_exon_variant	Exon 2 of 18	2		ENSP00000421783.1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00195 AC: 489 AN: 251316 Hom.: 0 AF XY: 0.00209 AC XY: 284 AN XY: 135816

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00351

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00256 AC: 3740 AN: 1461864 Hom.: 9 Cov.: 30 AF XY: 0.00251 AC XY: 1824 AN XY: 727232

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.00215

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74472

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.00158

EpiCase AF: 0.00278

EpiControl AF: 0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NSUN2: BP4, BS2 -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Apr 03, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Aug 24, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability, autosomal recessive 5 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.44
CADD	Benign	11
DANN	Benign	0.87

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: rs138716662; hg19: chr5-6632744;