rs762695606

Variant names:

• chr22-19915216-G-C
• rs762695606
• NM_006440.5:c.589C>G
• TXNRD2 p.His197Asp

Your query was ambiguous. Multiple possible variants found:

• chr22-19915216-G-C
• chr22-19915216-G-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006440.5(TXNRD2):​c.589C>G​(p.His197Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H197H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: TXNRD2 NM_006440.5 missense, splice_region
• Scores: Splicing: ADA: 0.0003816
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.745
• Publications: 0 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06870499).

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.589C>G	p.His197Asp	missense splice_region	Exon 7 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.586C>G	p.His196Asp	missense splice_region	Exon 7 of 17	NP_001339229.1
	TXNRD2	NM_001352301.2		c.499C>G	p.His167Asp	missense splice_region	Exon 7 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.589C>G	p.His197Asp	missense splice_region	Exon 7 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.586C>G	p.His196Asp	missense splice_region	Exon 7 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000400518.5	TSL:1	c.499C>G	p.His167Asp	missense splice_region	Exon 7 of 18	ENSP00000383362.1	A0A182DWF2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248060 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461468 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 726962

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

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

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111844

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000487 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.76
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		0.74
PrimateAI	Benign	0.39	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R		0.065
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00038
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs762695606;

hg19: chr22-19902739;