chr22-19895461-T-G

Variant names:

• chr22-19895461-T-G
• rs5992495
• NM_006440.5:c.895A>C

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.895A>C​(p.Ser299Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,613,808 control chromosomes in the GnomAD database, including 32,633 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S299C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.26 (7146 hom., cov: 33)
  • Exomes 𝑓: 0.17 (25487 hom.)
• Consequence: TXNRD2 NM_006440.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.812
• Publications: 42 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=1.9919422E-5).
• BP6: Variant 22-19895461-T-G is Benign according to our data. Variant chr22-19895461-T-G is described in ClinVar as Benign. ClinVar VariationId is 263411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 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.895A>C	p.Ser299Arg	missense	Exon 11 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.892A>C	p.Ser298Arg	missense	Exon 11 of 17	NP_001339229.1
	TXNRD2	NM_001352301.2		c.805A>C	p.Ser269Arg	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.895A>C	p.Ser299Arg	missense	Exon 11 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.892A>C	p.Ser298Arg	missense	Exon 11 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000400518.5	TSL:1	c.805A>C	p.Ser269Arg	missense	Exon 11 of 18	ENSP00000383362.1	A0A182DWF2

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39354 AN: 152086 Hom.: 7117 Cov.: 33

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.0586

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.235

GnomAD2 exomes AF: 0.179 AC: 44564 AN: 249058 AF XY: 0.178

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.0633

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.175 AC: 255419 AN: 1461604 Hom.: 25487 Cov.: 35 AF XY: 0.175 AC XY: 127304 AN XY: 727078

African (AFR) AF: 0.538 AC: 18016 AN: 33474

American (AMR) AF: 0.146 AC: 6513 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 5050 AN: 26134

East Asian (EAS) AF: 0.0514 AC: 2039 AN: 39700

South Asian (SAS) AF: 0.201 AC: 17334 AN: 86258

European-Finnish (FIN) AF: 0.129 AC: 6885 AN: 53178

Middle Eastern (MID) AF: 0.196 AC: 1128 AN: 5766

European-Non Finnish (NFE) AF: 0.169 AC: 187407 AN: 1111990

Other (OTH) AF: 0.183 AC: 11047 AN: 60384

GnomAD4 genome AF: 0.259 AC: 39452 AN: 152204 Hom.: 7146 Cov.: 33 AF XY: 0.253 AC XY: 18856 AN XY: 74434

African (AFR) AF: 0.511 AC: 21211 AN: 41504

American (AMR) AF: 0.193 AC: 2952 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 614 AN: 3468

East Asian (EAS) AF: 0.0587 AC: 304 AN: 5178

South Asian (SAS) AF: 0.200 AC: 967 AN: 4824

European-Finnish (FIN) AF: 0.126 AC: 1335 AN: 10628

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11461 AN: 67990

Other (OTH) AF: 0.236 AC: 500 AN: 2116

Alfa AF: 0.197 Hom.: 11743

Bravo AF: 0.275

TwinsUK AF: 0.177 AC: 657

ALSPAC AF: 0.167 AC: 644

ESP6500AA AF: 0.477 AC: 2062

ESP6500EA AF: 0.166 AC: 1415

ExAC AF: 0.188 AC: 22763

Asia WGS AF: 0.155 AC: 538 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.179

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (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	Benign	0.13
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.0080
DANN	Benign	0.25
DEOGEN2	Benign	0.047	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.018	T
MetaRNN	Benign	0.000020	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.23	N
PhyloP100		-0.81
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.015
Sift	Benign	0.42	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.050
MutPred		0.31		Loss of glycosylation at S299 (P = 0.0237)
MPC		0.23
ClinPred		0.00026	T
GERP RS		-2.8
Varity_R		0.056
Mutation Taster		=100/0	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: rs5992495; hg19: chr22-19882984; COSMIC: COSV57632911;