12-2828042-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_031474.3(NRIP2):c.584A>G(p.Glu195Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000947 in 1,613,310 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E195K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00097 ( 2 hom. )

Consequence

NRIP2
NM_031474.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.238

Variant links:

Genes affected

NRIP2 (HGNC:23078): (nuclear receptor interacting protein 2) Predicted to enable aspartic-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within Notch signaling pathway and negative regulation of transcription by RNA polymerase II. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NRIP2 links:

ITFG2 (HGNC:30879): (integrin alpha FG-GAP repeat containing 2) Involved in cellular response to amino acid starvation; cellular response to glucose starvation; and negative regulation of TORC1 signaling. Located in lysosomal membrane. Part of KICSTOR complex. [provided by Alliance of Genome Resources, Apr 2022]

ITFG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010444611).

BP6

Variant 12-2828042-T-C is Benign according to our data. Variant chr12-2828042-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2410441.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRIP2	NM_031474.3 link	c.584A>G	p.Glu195Gly	missense_variant	Exon 4 of 6	ENST00000337508.9	NP_113662.1	Q9BQI9-1
ITFG2	NR_130744.3 link	n.1573-2175T>C		intron_variant	Intron 12 of 13
ITFG2	NR_147202.2 link	n.1475-2792T>C		intron_variant	Intron 12 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRIP2	ENST00000337508.9 link	c.584A>G	p.Glu195Gly	missense_variant	Exon 4 of 6	1	NM_031474.3	ENSP00000337501.4		Q9BQI9-1

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000639

AC:

160

AN:

250208

Hom.:

AF XY:

0.000599

AC XY:

AN XY:

135264

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000814

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.0000929

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000970

AC:

1417

AN:

1461028

Hom.:

Cov.:

AF XY:

0.000947

AC XY:

688

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000986

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00115

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.000722

AC:

110

AN:

152282

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.000688

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000593

AC:

EpiCase

AF:

0.00131

EpiControl

AF:

0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 09, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.1

DANN

Benign

0.89

DEOGEN2

Benign

0.020

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.42

T;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.0

N;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.24

N;N

REVEL

Benign

0.036

Sift

Benign

0.46

T;T

Sift4G

Benign

0.72

T;.

Polyphen

0.0010

B;.

Vest4

0.10

MVP

0.34

MPC

0.034

ClinPred

0.0027

GERP RS

1.6

Varity_R

0.040

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

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