18-9886763-A-G

Variant names:

• chr18-9886763-A-G
• NM_032243.6:c.83A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032243.6(TXNDC2):​c.83A>G​(p.Asn28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TXNDC2 NM_032243.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.311
• Publications: 0 publications found

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]

ACMG classification

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=0.061124414).

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.83A>G	p.Asn28Ser	missense	Exon 2 of 2	NP_115619.4
	TXNDC2	NM_001098529.2		c.284A>G	p.Asn95Ser	missense	Exon 2 of 2	NP_001091999.1	A0A140VJY8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC2	ENST00000357775.6	TSL:1 MANE Select	c.83A>G	p.Asn28Ser	missense	Exon 2 of 2	ENSP00000350419.4	Q86VQ3-2
	TXNDC2	ENST00000306084.6	TSL:1	c.284A>G	p.Asn95Ser	missense	Exon 2 of 2	ENSP00000304908.6	Q86VQ3-1
	TXNDC2	ENST00000536353.2	TSL:5	c.83A>G	p.Asn28Ser	missense	Exon 2 of 3	ENSP00000437393.2	F5H6S7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.49
DANN	Benign	0.41
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.31
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.017
Sift	Uncertain	0.020	D
Sift4G	Benign	0.16	T
Polyphen		0.090	B
Vest4		0.021
MutPred		0.21		Gain of phosphorylation at N95 (P = 0.0034)
MVP		0.12
MPC		0.063
ClinPred		0.053	T
GERP RS		-1.1
Varity_R		0.050
gMVP		0.024
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

hg19: chr18-9886760;