20-21331792-C-T

Position:

• chr20-21331792-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000377191.5(XRN2):​c.674C>T​(p.Thr225Ile) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: XRN2 ENST00000377191.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRN2	NM_012255.5	c.674C>T	p.Thr225Ile	missense_variant	8/30	ENST00000377191.5	NP_036387.2
XRN2	NM_001317960.1	c.908C>T	p.Thr303Ile	missense_variant	8/30		NP_001304889.1
XRN2	XM_017027722.2	c.908C>T	p.Thr303Ile	missense_variant	8/17		XP_016883211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRN2	ENST00000377191.5	c.674C>T	p.Thr225Ile	missense_variant	8/30	1	NM_012255.5	ENSP00000366396.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 19, 2022

The c.674C>T (p.T225I) alteration is located in exon 8 (coding exon 8) of the XRN2 gene. This alteration results from a C to T substitution at nucleotide position 674, causing the threonine (T) at amino acid position 225 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	0.71
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.034	D
Polyphen		0.99	D
Vest4		0.79
MutPred		0.70		Loss of disorder (P = 0.0596);
MVP		0.25
MPC		1.1
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.56
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757988681; hg19: chr20-21312430;