rs387907191

Positions:

• chr5-6611067-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000264670.11(NSUN2):​c.1114C>T​(p.Gln372Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NSUN2 ENST00000264670.11 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.75

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-6611067-G-A is Pathogenic according to our data. Variant chr5-6611067-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31676.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSUN2	NM_017755.6	c.1114C>T	p.Gln372Ter	stop_gained	11/19	ENST00000264670.11	NP_060225.4
NSUN2	NM_001193455.2	c.1009C>T	p.Gln337Ter	stop_gained	10/18		NP_001180384.1
NSUN2	NR_037947.2	n.1094C>T		non_coding_transcript_exon_variant	10/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSUN2	ENST00000264670.11	c.1114C>T	p.Gln372Ter	stop_gained	11/19	1	NM_017755.6	ENSP00000264670	P2
NSUN2	ENST00000505892.5	n.1683C>T		non_coding_transcript_exon_variant	5/13	1
NSUN2	ENST00000506139.5	c.1009C>T	p.Gln337Ter	stop_gained	10/18	2		ENSP00000420957	A2
NSUN2	ENST00000504374.5	c.*420C>T		3_prime_UTR_variant, NMD_transcript_variant	10/18	2		ENSP00000421783

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal recessive 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 04, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.87
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs387907191; hg19: chr5-6611180;