22-36476703-T-G

Variant names:

• chr22-36476703-T-G
• rs2281082
• NM_012473.4:c.387+30A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012473.4(TXN2):​c.387+30A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 1,613,398 control chromosomes in the GnomAD database, including 492,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (45329 hom., cov: 30)
  • Exomes 𝑓: 0.77 (446846 hom.)
• Consequence: TXN2 NM_012473.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.571
• Publications: 24 publications found

Genes affected

TXN2 (HGNC:17772): (thioredoxin 2) This nuclear gene encodes a mitochondrial member of the thioredoxin family, a group of small multifunctional redox-active proteins. The encoded protein may play important roles in the regulation of the mitochondrial membrane potential and in protection against oxidant-induced apoptosis. [provided by RefSeq, Jul 2008]

TXN2 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 29

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• combined oxidative phosphorylation deficiency 29

  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=-0.89).
• BP6: Variant 22-36476703-T-G is Benign according to our data. Variant chr22-36476703-T-G is described in ClinVar as Benign. ClinVar VariationId is 1280669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012473.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXN2	NM_012473.4	MANE Select	c.387+30A>C		intron	N/A	NP_036605.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXN2	ENST00000216185.7	TSL:1 MANE Select	c.387+30A>C		intron	N/A	ENSP00000216185.2
	TXN2	ENST00000403313.5	TSL:3	c.387+30A>C		intron	N/A	ENSP00000385393.1
	TXN2	ENST00000416967.1	TSL:2	c.81+30A>C		intron	N/A	ENSP00000469160.1

Frequencies

GnomAD3 genomes AF: 0.764 AC: 116052 AN: 151890 Hom.: 45302 Cov.: 30

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.868

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.799

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.771

GnomAD2 exomes AF: 0.719 AC: 180359 AN: 250778 AF XY: 0.714

Gnomad AFR exome AF: 0.771

Gnomad AMR exome AF: 0.758

Gnomad ASJ exome AF: 0.789

Gnomad EAS exome AF: 0.266

Gnomad FIN exome AF: 0.724

Gnomad NFE exome AF: 0.811

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.774 AC: 1131615 AN: 1461390 Hom.: 446846 Cov.: 50 AF XY: 0.769 AC XY: 558835 AN XY: 727020

African (AFR) AF: 0.770 AC: 25778 AN: 33462

American (AMR) AF: 0.764 AC: 34135 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 20408 AN: 26114

East Asian (EAS) AF: 0.287 AC: 11392 AN: 39670

South Asian (SAS) AF: 0.558 AC: 48121 AN: 86206

European-Finnish (FIN) AF: 0.735 AC: 39199 AN: 53362

Middle Eastern (MID) AF: 0.770 AC: 4411 AN: 5726

European-Non Finnish (NFE) AF: 0.812 AC: 903032 AN: 1111778

Other (OTH) AF: 0.748 AC: 45139 AN: 60368

GnomAD4 genome AF: 0.764 AC: 116134 AN: 152008 Hom.: 45329 Cov.: 30 AF XY: 0.755 AC XY: 56100 AN XY: 74312

African (AFR) AF: 0.769 AC: 31847 AN: 41398

American (AMR) AF: 0.795 AC: 12137 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 2773 AN: 3470

East Asian (EAS) AF: 0.259 AC: 1342 AN: 5172

South Asian (SAS) AF: 0.520 AC: 2501 AN: 4814

European-Finnish (FIN) AF: 0.723 AC: 7645 AN: 10572

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.813 AC: 55249 AN: 67994

Other (OTH) AF: 0.765 AC: 1614 AN: 2110

Alfa AF: 0.797 Hom.: 64460

Bravo AF: 0.771

Asia WGS AF: 0.421 AC: 1465 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Combined oxidative phosphorylation deficiency 29 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.91
DANN	Benign	0.40
PhyloP100		-0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2281082; hg19: chr22-36872750; COSMIC: COSV53397663;