rs144584524

Variant names:

• chr22-19895540-G-A
• rs144584524
• NM_006440.5:c.816C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_006440.5(TXNRD2):​c.816C>T​(p.Gly272Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,613,244 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (8 hom.)
• Consequence: TXNRD2 NM_006440.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.15
• Publications: 2 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 22-19895540-G-A is Benign according to our data. Variant chr22-19895540-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 392163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.816C>T	p.Gly272Gly	synonymous	Exon 11 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.813C>T	p.Gly271Gly	synonymous	Exon 11 of 17	NP_001339229.1
	TXNRD2	NM_001352301.2		c.726C>T	p.Gly242Gly	synonymous	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.816C>T	p.Gly272Gly	synonymous	Exon 11 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.813C>T	p.Gly271Gly	synonymous	Exon 11 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000400518.5	TSL:1	c.726C>T	p.Gly242Gly	synonymous	Exon 11 of 18	ENSP00000383362.1	A0A182DWF2

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 381 AN: 152240 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00218 AC: 541 AN: 248344 AF XY: 0.00219

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00425

Gnomad NFE exome AF: 0.00359

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00278 AC: 4067 AN: 1460886 Hom.: 8 Cov.: 33 AF XY: 0.00275 AC XY: 1997 AN XY: 726782

African (AFR) AF: 0.000418 AC: 14 AN: 33478

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

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

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86258

European-Finnish (FIN) AF: 0.00448 AC: 235 AN: 52426

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00330 AC: 3671 AN: 1112006

Other (OTH) AF: 0.00142 AC: 86 AN: 60390

GnomAD4 genome AF: 0.00250 AC: 381 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.00236 AC XY: 176 AN XY: 74506

African (AFR) AF: 0.000553 AC: 23 AN: 41592

American (AMR) AF: 0.000784 AC: 12 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 68026

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

Alfa AF: 0.00319 Hom.: 0

Bravo AF: 0.00206

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00290

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Glucocorticoid deficiency 5 (1)
-	-	1	not specified (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	TXNRD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.2
DANN	Benign	0.77
PhyloP100		1.1
Mutation Taster		=99/1	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: rs144584524; hg19: chr22-19883063; COSMIC: COSV100538972;