Variant NM_001080516.2:c.726_*2delTTGCCAGATTTGCAATCAATAGCC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001080516.2(GRXCR2):c.726_*2delTTGCCAGATTTGCAATCAATAGCC(p.Pro242_Ter249delins???) variant causes a stop lost, conservative inframe deletion change. The variant allele was found at a frequency of 0.0000198 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

GRXCR2
NM_001080516.2 stop_lost, conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.87

Variant links:

Genes affected

GRXCR2 (HGNC:33862): (glutaredoxin and cysteine rich domain containing 2) This gene encodes a protein containing a glutaredoxin domain, which functions in protein S-glutathionylation. A mutation in this gene was found in a family with autoosomal recessive nonsyndromic sensorineural deafness-101. [provided by RefSeq, Jun 2014]

GRXCR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRXCR2	NM_001080516.2 link	c.726_*2delTTGCCAGATTTGCAATCAATAGCC	p.Pro242_Ter249delins???	stop_lost, conservative_inframe_deletion	Exon 3 of 3	ENST00000377976.3	NP_001073985.1	A6NFK2
GRXCR2	NM_001080516.2 link	c.725_*2delTTGCCAGATTTGCAATCAATAGCC		3_prime_UTR_variant	Exon 3 of 3	ENST00000377976.3	NP_001073985.1	A6NFK2
GRXCR2	XM_017009708.2 link	c.438_*2delTTGCCAGATTTGCAATCAATAGCC	p.Pro146_Ter153delins???	stop_lost, conservative_inframe_deletion	Exon 3 of 3		XP_016865197.1
GRXCR2	XM_017009708.2 link	c.437_*2delTTGCCAGATTTGCAATCAATAGCC		3_prime_UTR_variant	Exon 3 of 3		XP_016865197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GRXCR2	ENST00000377976.3 link	c.726_*2delTTGCCAGATTTGCAATCAATAGCC	p.Pro242_Ter249delins???	stop_lost, conservative_inframe_deletion	Exon 3 of 3	2	NM_001080516.2	ENSP00000367214.1	A6NFK2
GRXCR2	ENST00000377976 link	c.725_*2delTTGCCAGATTTGCAATCAATAGCC		3_prime_UTR_variant	Exon 3 of 3	2	NM_001080516.2	ENSP00000367214.1	A6NFK2
GRXCR2	ENST00000639411.1 link	c.321_*2delTTGCCAGATTTGCAATCAATAGCC	p.Pro107_Ter114delins???	stop_lost, conservative_inframe_deletion	Exon 4 of 4	5		ENSP00000491860.1	A0A1W2PQQ7
GRXCR2	ENST00000639411 link	c.320_*2delTTGCCAGATTTGCAATCAATAGCC		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000491860.1	A0A1W2PQQ7

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251190

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461532

Hom.:

AF XY:

0.0000234

AC XY:

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000960

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000491

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Pro242_249del) in the GRXCR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the GRXCR2 protein. This variant is present in population databases (rs772716837, ExAC 0.009%). This variant has not been reported in the literature in individuals with GRXCR2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over