12-2827663-C-G

Variant names:

• chr12-2827663-C-G
• NM_031474.3:c.715G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031474.3(NRIP2):​c.715G>C​(p.Glu239Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NRIP2 NM_031474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRIP2	NM_031474.3	c.715G>C	p.Glu239Gln	missense_variant	Exon 5 of 6	ENST00000337508.9	NP_113662.1
ITFG2	NR_130744.3	n.1573-2554C>G		intron_variant	Intron 12 of 13
ITFG2	NR_147202.2	n.1475-3171C>G		intron_variant	Intron 12 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRIP2	ENST00000337508.9	c.715G>C	p.Glu239Gln	missense_variant	Exon 5 of 6	1	NM_031474.3	ENSP00000337501.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.715G>C (p.E239Q) alteration is located in exon 5 (coding exon 5) of the NRIP2 gene. This alteration results from a G to C substitution at nucleotide position 715, causing the glutamic acid (E) at amino acid position 239 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.17
Sift	Benign	0.031	D
Sift4G	Benign	0.095	T
Polyphen		0.90	P
Vest4		0.59
MutPred		0.56		Loss of glycosylation at P238 (P = 0.0792);
MVP		0.28
MPC		0.21
ClinPred		0.92	D
GERP RS		3.7
Varity_R		0.11
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-2936829;