chr4-158833607-T-C

Position:

• chr4-158833607-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020840.3(FNIP2):​c.634T>C​(p.Cys212Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FNIP2 NM_020840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

Genes affected

FNIP2 (HGNC:29280): (folliculin interacting protein 2) This gene encodes a protein that binds to the tumor suppressor folliculin and to AMP-activated protein kinase (AMPK), and may play a role cellular metabolism and nutrient sensing by regulating the AMPK-mechanistic target of rapamycin signaling pathway. The encoded protein may also be involved in regulating the O6-methylguanine-induced apoptosis signaling pathway. This gene has a closely related paralog that encodes a protein with similar binding activities. Both related proteins also associate with the molecular chaperone heat shock protein-90 (Hsp90) and negatively regulate its ATPase activity and facilitate its association with folliculin. [provided by RefSeq, Jul 2017]

FNIP2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15714452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FNIP2	NM_020840.3	c.634T>C	p.Cys212Arg	missense_variant	6/17	ENST00000264433.11	NP_065891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FNIP2	ENST00000264433.11	c.634T>C	p.Cys212Arg	missense_variant	6/17	1	NM_020840.3	ENSP00000264433.6
FNIP2	ENST00000512986.5	c.703T>C	p.Cys235Arg	missense_variant	6/13	1		ENSP00000421488.1
FNIP2	ENST00000504704.6	n.653T>C		non_coding_transcript_exon_variant	6/6	1
FNIP2	ENST00000504715.1	c.139T>C	p.Cys47Arg	missense_variant	2/7	5		ENSP00000420841.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.634T>C (p.C212R) alteration is located in exon 6 (coding exon 6) of the FNIP2 gene. This alteration results from a T to C substitution at nucleotide position 634, causing the cysteine (C) at amino acid position 212 to be replaced by an arginine (R). 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	0.23
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.045	T;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.0096
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N;N;D
REVEL	Benign	0.11
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.40	B;B;.
Vest4		0.73
MutPred		0.22		Gain of glycosylation at T214 (P = 0.0465);.;.;
MVP		0.093
MPC		0.58
ClinPred		0.31	T
GERP RS		2.9
Varity_R		0.36
gMVP		0.75

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: chr4-159754759;