rs4646310

Positions:

• chr22-19941283-G-A
• chr22-19941283-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000400521.7(TXNRD2):​c.103+418C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 152,190 control chromosomes in the GnomAD database, including 1,906 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1906 hom., cov: 32)
• Consequence: TXNRD2 ENST00000400521.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.650

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.103+418C>T		intron_variant		ENST00000400521.7	NP_006431.2
TXNRD2	NM_001282512.3	c.103+418C>T		intron_variant			NP_001269441.1
TXNRD2	NM_001352300.2	c.103+418C>T		intron_variant			NP_001339229.1
TXNRD2	NR_147957.2	n.118+418C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.103+418C>T		intron_variant		1	NM_006440.5	ENSP00000383365	P4

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21966 AN: 152072 Hom.: 1907 Cov.: 32

Gnomad AFR AF: 0.0746

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0307

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.166

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.144 AC: 21971 AN: 152190 Hom.: 1906 Cov.: 32 AF XY: 0.141 AC XY: 10510 AN XY: 74412

Gnomad4 AFR AF: 0.0747

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.0307

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.164

Alfa AF: 0.179 Hom.: 3321

Bravo AF: 0.142

Asia WGS AF: 0.0620 AC: 217 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.98
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs4646310; hg19: chr22-19928806;