12-2830804-C-G

Variant names:

• chr12-2830804-C-G
• rs1036210657
• NM_031474.3:c.399G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031474.3(NRIP2):​c.399G>C​(p.Gln133His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NRIP2 NM_031474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.395
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11339104).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031474.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRIP2	NM_031474.3	MANE Select	c.399G>C	p.Gln133His	missense	Exon 2 of 6	NP_113662.1	Q9BQI9-1
	ITFG2	NR_130744.3		n.2160C>G		non_coding_transcript_exon	Exon 13 of 14
	ITFG2	NR_147202.2		n.1475-30C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRIP2	ENST00000337508.9	TSL:1 MANE Select	c.399G>C	p.Gln133His	missense	Exon 2 of 6	ENSP00000337501.4	Q9BQI9-1
	NRIP2	ENST00000542990.5	TSL:4	c.249G>C	p.Gln83His	missense	Exon 3 of 5	ENSP00000446283.1	F5H2G5
	NRIP2	ENST00000542386.1	TSL:4	c.249G>C	p.Gln83His	missense	Exon 3 of 4	ENSP00000438338.1	F5H065

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461600 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727106

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111884

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.40
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.082
Sift	Uncertain	0.021	D
Sift4G	Benign	0.074	T
Polyphen		0.95	P
Vest4		0.39
MutPred		0.23		Gain of helix (P = 0.132)
MVP		0.16
MPC		0.15
ClinPred		0.54	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.15
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1036210657; hg19: chr12-2939970;