Genetic Variant NM_032243.6:c.499C>A (chr18-9887179-C-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_032243.6(TXNDC2):c.499C>A(p.Pro167Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,585,672 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0041 ( 18 hom. )

Consequence

TXNDC2
NM_032243.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.51

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004492551).

BP6

Variant 18-9887179-C-A is Benign according to our data. Variant chr18-9887179-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2648567.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 18 AR gene

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.499C>A	p.Pro167Thr	missense	Exon 2 of 2	NP_115619.4
	TXNDC2	NM_001098529.2		c.700C>A	p.Pro234Thr	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.499C>A	p.Pro167Thr	missense	Exon 2 of 2	ENSP00000350419.4	Q86VQ3-2
TXNDC2	ENST00000306084.6	TSL:1	c.700C>A	p.Pro234Thr	missense	Exon 2 of 2	ENSP00000304908.6	Q86VQ3-1
TXNDC2	ENST00000536353.2	TSL:5	c.328+171C>A		intron	N/A	ENSP00000437393.2	F5H6S7

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

428

AN:

150538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000417

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000792

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00455

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00509

Gnomad OTH

AF:

0.00195

GnomAD2 exomes

AF:

0.00354

AC:

889

AN:

251340

AF XY:

0.00339

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00439

Gnomad NFE exome

AF:

0.00659

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00407

AC:

5843

AN:

1435032

Hom.:

Cov.:

136

AF XY:

0.00396

AC XY:

2824

AN XY:

713824

show subpopulations

African (AFR)

AF:

0.000516

AC:

AN:

32974

American (AMR)

AF:

0.000276

AC:

AN:

43556

Ashkenazi Jewish (ASJ)

AF:

0.000728

AC:

AN:

24728

East Asian (EAS)

AF:

0.00

AC:

AN:

39032

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84382

European-Finnish (FIN)

AF:

0.00463

AC:

246

AN:

53150

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.00492

AC:

5379

AN:

1092886

Other (OTH)

AF:

0.00288

AC:

169

AN:

58708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

401

802

1202

1603

2004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00284

AC:

428

AN:

150640

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

209

AN XY:

73560

show subpopulations

African (AFR)

AF:

0.000416

AC:

AN:

40894

American (AMR)

AF:

0.000791

AC:

AN:

15164

Ashkenazi Jewish (ASJ)

AF:

0.000866

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5034

South Asian (SAS)

AF:

0.00

AC:

AN:

4734

European-Finnish (FIN)

AF:

0.00455

AC:

AN:

10340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00509

AC:

345

AN:

67752

Other (OTH)

AF:

0.00193

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00351

Hom.:

Bravo

AF:

0.00241

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00570

AC:

ExAC

AF:

0.00441

AC:

535

EpiCase

AF:

0.00420

EpiControl

AF:

0.00409

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.21

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.062

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.32

M_CAP

Benign

0.0086

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.3

PhyloP100

-1.5

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.4

REVEL

Benign

0.079

Sift

Benign

0.047

Sift4G

Benign

0.089

Polyphen

0.95

Vest4

0.061

MVP

0.55

MPC

0.054

ClinPred

0.027

GERP RS

0.57

Varity_R

0.046

gMVP

0.064

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over