22-19880654-C-T

Variant names:

• chr22-19880654-C-T
• rs192869629
• NM_006440.5:c.1150G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006440.5(TXNRD2):​c.1150G>A​(p.Gly384Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00619 in 1,613,390 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G384R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0070 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (79 hom.)
• Consequence: TXNRD2 NM_006440.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.33
• Publications: 7 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055096447).
• BP6: Variant 22-19880654-C-T is Benign according to our data. Variant chr22-19880654-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR,Unknown gene

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.1150G>A	p.Gly384Ser	missense	Exon 13 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.1147G>A	p.Gly383Ser	missense	Exon 13 of 17	NP_001339229.1
	TXNRD2	NM_001352301.2		c.1060G>A	p.Gly354Ser	missense	Exon 13 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.1150G>A	p.Gly384Ser	missense	Exon 13 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.1147G>A	p.Gly383Ser	missense	Exon 13 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000400518.5	TSL:1	c.1060G>A	p.Gly354Ser	missense	Exon 13 of 18	ENSP00000383362.1	A0A182DWF2

Frequencies

GnomAD3 genomes AF: 0.00705 AC: 1073 AN: 152208 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00795

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00760 AC: 1891 AN: 248654 AF XY: 0.00709

Gnomad AFR exome AF: 0.000390

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.0381

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.00843

Gnomad OTH exome AF: 0.00845

GnomAD4 exome AF: 0.00610 AC: 8906 AN: 1461064 Hom.: 79 Cov.: 31 AF XY: 0.00599 AC XY: 4352 AN XY: 726844

African (AFR) AF: 0.000358 AC: 12 AN: 33478

American (AMR) AF: 0.00282 AC: 126 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0425 AC: 1110 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86254

European-Finnish (FIN) AF: 0.0185 AC: 975 AN: 52658

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00560 AC: 6228 AN: 1111960

Other (OTH) AF: 0.00689 AC: 416 AN: 60388

GnomAD4 genome AF: 0.00704 AC: 1073 AN: 152326 Hom.: 7 Cov.: 33 AF XY: 0.00749 AC XY: 558 AN XY: 74480

African (AFR) AF: 0.000553 AC: 23 AN: 41576

American (AMR) AF: 0.00686 AC: 105 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 154 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0205 AC: 218 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00795 AC: 541 AN: 68030

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00756 Hom.: 26

Bravo AF: 0.00547

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000724 AC: 3

ESP6500EA AF: 0.00570 AC: 48

ExAC AF: 0.00764 AC: 924

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00670

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.3
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Benign	0.17	T
Polyphen		0.37	B
Vest4		0.34
MVP		0.56
MPC		0.21
ClinPred		0.014	T
GERP RS		4.3
Varity_R		0.080
Mutation Taster		=100/0	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

dbSNP: rs192869629; hg19: chr22-19868177;