22-19915788-C-T

Variant names:

• chr22-19915788-C-T
• rs138462062
• NM_006440.5:c.505G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000400521.7(TXNRD2):​c.505G>A​(p.Gly169Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,614,176 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G169G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: TXNRD2 ENST00000400521.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.39
• Publications: 3 publications found

Genes affected

TXNRD2 (HGNC:18155): (thioredoxin reductase 2) The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes a mitochondrial form important for scavenging reactive oxygen species in mitochondria. It functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternatively spliced transcript variants encoding different isoforms, including a few localized in the cytosol and some lacking the C-terminal Sec residue, have been found for this gene. [provided by RefSeq, Jun 2017]

TXNRD2 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial glucocorticoid deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• glucocorticoid deficiency 5

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007433504).
• BP6: Variant 22-19915788-C-T is Benign according to our data. Variant chr22-19915788-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 414277.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000400521.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	NM_006440.5	MANE Select	c.505G>A	p.Gly169Ser	missense	Exon 6 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.502G>A	p.Gly168Ser	missense	Exon 6 of 17	NP_001339229.1
	TXNRD2	NM_001352301.2		c.415G>A	p.Gly139Ser	missense	Exon 6 of 18	NP_001339230.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.505G>A	p.Gly169Ser	missense	Exon 6 of 18	ENSP00000383365.1
	TXNRD2	ENST00000400519.6	TSL:1	c.502G>A	p.Gly168Ser	missense	Exon 6 of 17	ENSP00000383363.1
	TXNRD2	ENST00000400518.5	TSL:1	c.415G>A	p.Gly139Ser	missense	Exon 6 of 18	ENSP00000383362.1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000280 AC: 70 AN: 249578 AF XY: 0.000214

Gnomad AFR exome AF: 0.00387

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 186 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000976 AC XY: 71 AN XY: 727246

African (AFR) AF: 0.00487 AC: 163 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 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: 0.00000360 AC: 4 AN: 1112010

Other (OTH) AF: 0.000215 AC: 13 AN: 60396

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74456

African (AFR) AF: 0.00407 AC: 169 AN: 41550

American (AMR) AF: 0.000458 AC: 7 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000400 Hom.: 2

Bravo AF: 0.00115

ESP6500AA AF: 0.00327 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000281 AC: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	TXNRD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.28	N
PhyloP100		3.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.11
Sift	Benign	0.16	T
Sift4G	Benign	0.40	T
Polyphen		0.75	P
Vest4		0.47
MVP		0.48
MPC		0.22
ClinPred		0.017	T
GERP RS		3.9
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs138462062; hg19: chr22-19903311;