20-21340834-G-A

Position:

• chr20-21340834-G-A

Variant summary

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

The NM_012255.5(XRN2):​c.1392G>A​(p.Met464Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: XRN2 NM_012255.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.04

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRN2	NM_012255.5	c.1392G>A	p.Met464Ile	missense_variant	15/30	ENST00000377191.5	NP_036387.2
XRN2	NM_001317960.1	c.1626G>A	p.Met542Ile	missense_variant	15/30		NP_001304889.1
XRN2	XM_017027722.2	c.1626G>A	p.Met542Ile	missense_variant	15/17		XP_016883211.1
XRN2	XM_017027723.3	c.120G>A	p.Met40Ile	missense_variant	3/18		XP_016883212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRN2	ENST00000377191.5	c.1392G>A	p.Met464Ile	missense_variant	15/30	1	NM_012255.5	ENSP00000366396	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Sep 20, 2023

The c.1392G>A (p.M464I) alteration is located in exon 15 (coding exon 15) of the XRN2 gene. This alteration results from a G to A substitution at nucleotide position 1392, causing the methionine (M) at amino acid position 464 to be replaced by an isoleucine (I). 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	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.063	T
Eigen	Benign	0.066
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.24
Sift	Benign	0.12	T
Sift4G	Benign	0.34	T
Polyphen		0.091	B
Vest4		0.71
MutPred		0.29		Loss of MoRF binding (P = 0.1399);
MVP		0.41
MPC		0.37
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.38
gMVP		0.56

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: rs2038362644; hg19: chr20-21321472;