chr22-19895498-C-G

Variant names:

• chr22-19895498-C-G
• rs201503021
• NM_006440.5:c.858G>C

Variant summary

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

The NM_006440.5(TXNRD2):​c.858G>C​(p.Arg286Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. R286R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: TXNRD2 NM_006440.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.0150
• 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=0.014597446).
• BP6: Variant 22-19895498-C-G is Benign according to our data. Variant chr22-19895498-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 414282.

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.858G>C	p.Arg286Ser	missense	Exon 11 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.855G>C	p.Arg285Ser	missense	Exon 11 of 17	NP_001339229.1
	TXNRD2	NM_001352301.2		c.768G>C	p.Arg256Ser	missense	Exon 11 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.858G>C	p.Arg286Ser	missense	Exon 11 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.855G>C	p.Arg285Ser	missense	Exon 11 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000400518.5	TSL:1	c.768G>C	p.Arg256Ser	missense	Exon 11 of 18	ENSP00000383362.1	A0A182DWF2

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000634 AC: 158 AN: 249064 AF XY: 0.000718

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0000935

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.00107 AC: 1557 AN: 1461578 Hom.: 0 Cov.: 33 AF XY: 0.00108 AC XY: 788 AN XY: 727096

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000224 AC: 10 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: 0.000765 AC: 66 AN: 86256

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53114

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

European-Non Finnish (NFE) AF: 0.00126 AC: 1397 AN: 1112010

Other (OTH) AF: 0.00111 AC: 67 AN: 60392

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000578 AC XY: 43 AN XY: 74358

African (AFR) AF: 0.000241 AC: 10 AN: 41448

American (AMR) AF: 0.000327 AC: 5 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68030

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000670 Hom.: 0

Bravo AF: 0.000740

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00118 AC: 10

ExAC AF: 0.000644 AC: 78

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Primary dilated cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	TXNRD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.015
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.058
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.016	D
Polyphen		0.44	B
Vest4		0.14
MutPred		0.48		Loss of MoRF binding (P = 0.0207)
MVP		0.43
MPC		0.24
ClinPred		0.018	T
GERP RS		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
Mutation Taster		=83/17	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: rs201503021; hg19: chr22-19883021;