rs5748469

Variant names:

• chr22-19919576-C-A
• rs5748469
• NM_006440.5:c.196G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006440.5(TXNRD2):​c.196G>T​(p.Ala66Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,560,344 control chromosomes in the GnomAD database, including 123,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A66T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.37 (11774 hom., cov: 29)
  • Exomes 𝑓: 0.38 (112225 hom.)
• Consequence: TXNRD2 NM_006440.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.82
• Publications: 65 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.981186E-6).
• BP6: Variant 22-19919576-C-A is Benign according to our data. Variant chr22-19919576-C-A is described in ClinVar as Benign. ClinVar VariationId is 263343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006440.5. 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
	TXNRD2	NM_006440.5	MANE Select	c.196G>T	p.Ala66Ser	missense	Exon 3 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.193G>T	p.Ala65Ser	missense	Exon 3 of 17	NP_001339229.1
	TXNRD2	NM_001352301.2		c.106G>T	p.Ala36Ser	missense	Exon 3 of 18	NP_001339230.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.196G>T	p.Ala66Ser	missense	Exon 3 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.193G>T	p.Ala65Ser	missense	Exon 3 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000400518.5	TSL:1	c.106G>T	p.Ala36Ser	missense	Exon 3 of 18	ENSP00000383362.1	A0A182DWF2

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56077 AN: 151572 Hom.: 11759 Cov.: 29

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.862

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.371

GnomAD2 exomes AF: 0.449 AC: 77201 AN: 172046 AF XY: 0.442

Gnomad AFR exome AF: 0.226

Gnomad AMR exome AF: 0.612

Gnomad ASJ exome AF: 0.420

Gnomad EAS exome AF: 0.856

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.385 AC: 541818 AN: 1408654 Hom.: 112225 Cov.: 40 AF XY: 0.388 AC XY: 270033 AN XY: 696196

African (AFR) AF: 0.228 AC: 7284 AN: 32008

American (AMR) AF: 0.597 AC: 21989 AN: 36802

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 10695 AN: 25230

East Asian (EAS) AF: 0.853 AC: 30697 AN: 35980

South Asian (SAS) AF: 0.508 AC: 40478 AN: 79742

European-Finnish (FIN) AF: 0.468 AC: 23413 AN: 49980

Middle Eastern (MID) AF: 0.347 AC: 1981 AN: 5706

European-Non Finnish (NFE) AF: 0.352 AC: 381499 AN: 1084768

Other (OTH) AF: 0.407 AC: 23782 AN: 58438

GnomAD4 genome AF: 0.370 AC: 56120 AN: 151690 Hom.: 11774 Cov.: 29 AF XY: 0.384 AC XY: 28479 AN XY: 74070

African (AFR) AF: 0.239 AC: 9905 AN: 41418

American (AMR) AF: 0.497 AC: 7588 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1530 AN: 3468

East Asian (EAS) AF: 0.862 AC: 4366 AN: 5066

South Asian (SAS) AF: 0.532 AC: 2561 AN: 4812

European-Finnish (FIN) AF: 0.475 AC: 4993 AN: 10514

Middle Eastern (MID) AF: 0.349 AC: 102 AN: 292

European-Non Finnish (NFE) AF: 0.352 AC: 23895 AN: 67836

Other (OTH) AF: 0.372 AC: 786 AN: 2112

Alfa AF: 0.378 Hom.: 25149

Bravo AF: 0.370

TwinsUK AF: 0.340 AC: 1260

ALSPAC AF: 0.351 AC: 1353

ESP6500AA AF: 0.223 AC: 929

ESP6500EA AF: 0.331 AC: 2791

ExAC AF: 0.327 AC: 36311

Asia WGS AF: 0.645 AC: 2241 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Glucocorticoid deficiency 5 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.000010	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		2.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.33
MPC		0.75
ClinPred		0.094	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
Mutation Taster		=98/2	polymorphism (auto)

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

dbSNP: rs5748469; hg19: chr22-19907099; COSMIC: COSV57632581; COSMIC: COSV57632581;