Genetic Variant TXNDC2:p.Pro149Ser (chr18-9887125-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032243.6(TXNDC2):c.445C>T(p.Pro149Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,586,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

TXNDC2
NM_032243.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.29

Variant links:

Genes affected

TXNDC2 (HGNC:16470): (thioredoxin domain containing 2) Enables thioredoxin-disulfide reductase activity. Predicted to be involved in cell differentiation and cellular oxidant detoxification. Predicted to act upstream of or within cellular response to reactive oxygen species and flagellated sperm motility. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TXNDC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044799358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNDC2	NM_032243.6 link	c.445C>T	p.Pro149Ser	missense_variant	Exon 2 of 2	ENST00000357775.6	NP_115619.4	Q86VQ3-2
TXNDC2	NM_001098529.2 link	c.646C>T	p.Pro216Ser	missense_variant	Exon 2 of 2		NP_001091999.1	Q86VQ3-1A0A140VJY8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNDC2	ENST00000357775.6 link	c.445C>T	p.Pro149Ser	missense_variant	Exon 2 of 2	1	NM_032243.6	ENSP00000350419.4		Q86VQ3-2

Frequencies

GnomAD3 genomes

AF:

0.0000992

AC:

AN:

141170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000139

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000170

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251392

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000146

AC:

211

AN:

1445012

Hom.:

Cov.:

130

AF XY:

0.000138

AC XY:

AN XY:

718808

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000169

Gnomad4 OTH exome

AF:

0.000320

GnomAD4 genome

AF:

0.0000991

AC:

AN:

141296

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

68978

show subpopulations

Gnomad4 AFR

AF:

0.0000265

Gnomad4 AMR

AF:

0.000139

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000170

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000166

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646C>T (p.P216S) alteration is located in exon 2 (coding exon 2) of the TXNDC2 gene. This alteration results from a C to T substitution at nucleotide position 646, causing the proline (P) at amino acid position 216 to be replaced by a serine (S). 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

0.095

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.019

DANN

Benign

0.33

DEOGEN2

Benign

0.035

.;.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0051

LIST_S2

Benign

0.15

T;T;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.045

T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.7

L;.;L

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.3

.;N;N

REVEL

Benign

0.26

Sift

Benign

0.33

.;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.15

.;.;B

Vest4

0.062

MVP

0.30

MPC

0.11

ClinPred

0.085

GERP RS

-5.0

Varity_R

0.022

gMVP

0.045

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over