Genetic Variant TXNDC2:p.Pro149Thr (chr18-9887125-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032243.6(TXNDC2):c.445C>A(p.Pro149Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P149S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Failed GnomAD Quality Control

Consequence

TXNDC2
NM_032243.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.29

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046579838).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032243.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC2	NM_032243.6	MANE Select	c.445C>A	p.Pro149Thr	missense	Exon 2 of 2	NP_115619.4
	TXNDC2	NM_001098529.2		c.646C>A	p.Pro216Thr	missense	Exon 2 of 2	NP_001091999.1	A0A140VJY8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TXNDC2	ENST00000357775.6	TSL:1 MANE Select	c.445C>A	p.Pro149Thr	missense	Exon 2 of 2	ENSP00000350419.4	Q86VQ3-2
TXNDC2	ENST00000306084.6	TSL:1	c.646C>A	p.Pro216Thr	missense	Exon 2 of 2	ENSP00000304908.6	Q86VQ3-1
TXNDC2	ENST00000536353.2	TSL:5	c.328+117C>A		intron	N/A	ENSP00000437393.2	F5H6S7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

141162

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

130

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

141162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68846

African (AFR)

AF:

0.00

AC:

AN:

37564

American (AMR)

AF:

0.00

AC:

AN:

14386

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3356

East Asian (EAS)

AF:

0.00

AC:

AN:

4394

South Asian (SAS)

AF:

0.00

AC:

AN:

4278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64730

Other (OTH)

AF:

0.00

AC:

AN:

1914

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.0030

(source)

DANN

Benign

0.11

DEOGEN2

Benign

0.025

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.15

M_CAP

Benign

0.050

MetaRNN

Benign

0.047

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.81

PhyloP100

-2.3

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.64

REVEL

Benign

0.25

Sift

Benign

1.0

Sift4G

Benign

0.14

Polyphen

0.013

Vest4

0.023

MutPred

0.18

Gain of phosphorylation at P216 (P = 0.0357)

MVP

0.29

MPC

0.057

ClinPred

0.060

GERP RS

-5.0

Varity_R

0.025

gMVP

0.042

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over