20-21333572-G-T

Position:

• chr20-21333572-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012255.5(XRN2):​c.887G>T​(p.Cys296Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: XRN2 NM_012255.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.767

Genes affected

XRN2 (HGNC:12836): (5'-3' exoribonuclease 2) This gene encodes a 5'-3' exonuclease that promotes transcription termination at cotranscriptional cleavage sites. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08000654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRN2	NM_012255.5	c.887G>T	p.Cys296Phe	missense_variant	10/30	ENST00000377191.5	NP_036387.2
XRN2	NM_001317960.1	c.1121G>T	p.Cys374Phe	missense_variant	10/30		NP_001304889.1
XRN2	XM_017027722.2	c.1121G>T	p.Cys374Phe	missense_variant	10/17		XP_016883211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRN2	ENST00000377191.5	c.887G>T	p.Cys296Phe	missense_variant	10/30	1	NM_012255.5	ENSP00000366396	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461356 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726880

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2023

The c.887G>T (p.C296F) alteration is located in exon 10 (coding exon 10) of the XRN2 gene. This alteration results from a G to T substitution at nucleotide position 887, causing the cysteine (C) at amino acid position 296 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Benign	0.85
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.11
Sift	Benign	0.38	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.45
MutPred		0.28		Gain of phosphorylation at S293 (P = 0.1382);
MVP		0.043
MPC		0.45
ClinPred		0.13	T
GERP RS		2.4
Varity_R		0.080
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs2038244381; hg19: chr20-21314210;