NM_006440.5:c.662+63T>C

Variant names:

• chr22-19911314-A-G
• rs885987
• NM_006440.5:c.662+63T>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.662+63T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,310,984 control chromosomes in the GnomAD database, including 244,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33451 hom., cov: 31)
  • Exomes 𝑓: 0.60 (211536 hom.)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.58
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-19911314-A-G is Benign according to our data. Variant chr22-19911314-A-G is described in ClinVar as Benign. ClinVar VariationId is 678039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 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.662+63T>C		intron	N/A	NP_006431.2
	TXNRD2	NM_001352300.2		c.659+63T>C		intron	N/A	NP_001339229.1
	TXNRD2	NM_001352301.2		c.572+63T>C		intron	N/A	NP_001339230.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.662+63T>C		intron	N/A	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.659+63T>C		intron	N/A	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000400518.5	TSL:1	c.572+63T>C		intron	N/A	ENSP00000383362.1	A0A182DWF2

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99332 AN: 151876 Hom.: 33397 Cov.: 31

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.922

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.633

GnomAD4 exome AF: 0.596 AC: 690983 AN: 1158990 Hom.: 211536 Cov.: 16 AF XY: 0.599 AC XY: 353590 AN XY: 590354

African (AFR) AF: 0.778 AC: 21363 AN: 27464

American (AMR) AF: 0.774 AC: 33915 AN: 43816

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 15649 AN: 24244

East Asian (EAS) AF: 0.913 AC: 34860 AN: 38194

South Asian (SAS) AF: 0.712 AC: 56731 AN: 79706

European-Finnish (FIN) AF: 0.616 AC: 32668 AN: 53008

Middle Eastern (MID) AF: 0.562 AC: 2900 AN: 5162

European-Non Finnish (NFE) AF: 0.552 AC: 461915 AN: 837068

Other (OTH) AF: 0.616 AC: 30982 AN: 50328

GnomAD4 genome AF: 0.654 AC: 99448 AN: 151994 Hom.: 33451 Cov.: 31 AF XY: 0.661 AC XY: 49122 AN XY: 74298

African (AFR) AF: 0.771 AC: 31979 AN: 41460

American (AMR) AF: 0.710 AC: 10855 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 2238 AN: 3468

East Asian (EAS) AF: 0.923 AC: 4771 AN: 5170

South Asian (SAS) AF: 0.738 AC: 3555 AN: 4816

European-Finnish (FIN) AF: 0.618 AC: 6510 AN: 10536

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37574 AN: 67944

Other (OTH) AF: 0.636 AC: 1339 AN: 2106

Alfa AF: 0.620 Hom.: 11096

Bravo AF: 0.667

Asia WGS AF: 0.805 AC: 2799 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.12
DANN	Benign	0.61
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs885987; hg19: chr22-19898837;