Genetic Variant NM_032243.6:c.344C>G (chr18-9887024-C-G) – 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.344C>G(p.Ala115Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,455,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TXNDC2
NM_032243.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.69

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=0.054205596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNDC2	NM_032243.6 link	c.344C>G	p.Ala115Gly	missense_variant	Exon 2 of 2	ENST00000357775.6	NP_115619.4	Q86VQ3-2
TXNDC2	NM_001098529.2 link	c.545C>G	p.Ala182Gly	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.344C>G	p.Ala115Gly	missense_variant	Exon 2 of 2	1	NM_032243.6	ENSP00000350419.4		Q86VQ3-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251424

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1455692

Hom.:

Cov.:

129

AF XY:

0.00000138

AC XY:

AN XY:

724218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000907

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.545C>G (p.A182G) alteration is located in exon 2 (coding exon 2) of the TXNDC2 gene. This alteration results from a C to G substitution at nucleotide position 545, causing the alanine (A) at amino acid position 182 to be replaced by a glycine (G). 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

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.036

DANN

Benign

0.43

DEOGEN2

Benign

0.034

.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.33

T;T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.054

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.;L

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.85

.;N;N

REVEL

Benign

0.012

Sift

Benign

0.064

.;T;D

Sift4G

Benign

0.48

T;T;T

Polyphen

0.27

.;.;B

Vest4

0.094

MutPred

0.13

Gain of glycosylation at K181 (P = 0.1256);.;Gain of glycosylation at K181 (P = 0.1256);

MVP

0.22

MPC

0.077

ClinPred

0.061

GERP RS

-1.4

Varity_R

0.055

gMVP

0.018

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