rs35544159

Variant names:

• chr22-19880705-G-A
• rs35544159
• NM_006440.5:c.1099C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006440.5(TXNRD2):​c.1099C>T​(p.Leu367Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,612,016 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (55 hom.)
• Consequence: TXNRD2 NM_006440.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.16
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 22-19880705-G-A is Benign according to our data. Variant chr22-19880705-G-A is described in ClinVar as Benign. ClinVar VariationId is 263358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0148 (2235/151290) while in subpopulation AFR AF = 0.043 (1758/40864). AF 95% confidence interval is 0.0413. There are 40 homozygotes in GnomAd4. There are 1049 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AD,Unknown,AR 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.1099C>T	p.Leu367Leu	synonymous	Exon 13 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.1096C>T	p.Leu366Leu	synonymous	Exon 13 of 17	NP_001339229.1
	TXNRD2	NM_001352301.2		c.1009C>T	p.Leu337Leu	synonymous	Exon 13 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.1099C>T	p.Leu367Leu	synonymous	Exon 13 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.1096C>T	p.Leu366Leu	synonymous	Exon 13 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000400518.5	TSL:1	c.1009C>T	p.Leu337Leu	synonymous	Exon 13 of 18	ENSP00000383362.1	A0A182DWF2

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2231 AN: 151176 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0139

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0129

Gnomad NFE AF: 0.00321

Gnomad OTH AF: 0.0159

GnomAD2 exomes AF: 0.00660 AC: 1635 AN: 247832 AF XY: 0.00595

Gnomad AFR exome AF: 0.0470

Gnomad AMR exome AF: 0.00670

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000608

Gnomad NFE exome AF: 0.00401

Gnomad OTH exome AF: 0.00748

GnomAD4 exome AF: 0.00410 AC: 5993 AN: 1460726 Hom.: 55 Cov.: 36 AF XY: 0.00389 AC XY: 2827 AN XY: 726684

African (AFR) AF: 0.0476 AC: 1593 AN: 33470

American (AMR) AF: 0.00734 AC: 328 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 425 AN: 26132

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

South Asian (SAS) AF: 0.000858 AC: 74 AN: 86246

European-Finnish (FIN) AF: 0.000726 AC: 38 AN: 52376

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5762

European-Non Finnish (NFE) AF: 0.00269 AC: 2987 AN: 1111954

Other (OTH) AF: 0.00754 AC: 455 AN: 60376

GnomAD4 genome AF: 0.0148 AC: 2235 AN: 151290 Hom.: 40 Cov.: 33 AF XY: 0.0142 AC XY: 1049 AN XY: 73974

African (AFR) AF: 0.0430 AC: 1758 AN: 40864

American (AMR) AF: 0.0111 AC: 169 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 48 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10608

Middle Eastern (MID) AF: 0.0139 AC: 4 AN: 288

European-Non Finnish (NFE) AF: 0.00321 AC: 218 AN: 67860

Other (OTH) AF: 0.0158 AC: 33 AN: 2094

Alfa AF: 0.00947 Hom.: 9

Bravo AF: 0.0172

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00356

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
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		2.2
PromoterAI		-0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs35544159; hg19: chr22-19868228;