rs267606877

Variant names:

• chr14-104703343-T-C
• rs267606877
• NM_022489.4:c.556T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_022489.4(INF2):​c.556T>C​(p.Ser186Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S186S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 1.84
• Publications: 11 publications found

Genes affected

INF2 (HGNC:23791): (inverted formin 2) This gene represents a member of the formin family of proteins. It is considered a diaphanous formin due to the presence of a diaphanous inhibitory domain located at the N-terminus of the encoded protein. Studies of a similar mouse protein indicate that the protein encoded by this locus may function in polymerization and depolymerization of actin filaments. Mutations at this locus have been associated with focal segmental glomerulosclerosis 5.[provided by RefSeq, Aug 2010]

INF2 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease dominant intermediate E

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• focal segmental glomerulosclerosis 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_022489.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783
• PP5: Variant 14-104703343-T-C is Pathogenic according to our data. Variant chr14-104703343-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1050.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INF2	NM_022489.4	c.556T>C	p.Ser186Pro	missense_variant	Exon 4 of 23	ENST00000392634.9	NP_071934.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9	c.556T>C	p.Ser186Pro	missense_variant	Exon 4 of 23	5	NM_022489.4	ENSP00000376410.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000655 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Focal segmental glomerulosclerosis 5 Pathogenic:1

Jan 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

INF2-related disorder Pathogenic:1

Jun 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The INF2 c.556T>C variant is predicted to result in the amino acid substitution p.Ser186Pro. This variant has been reported to be pathogenic for autosomal dominant focal segmental glomerulosclerosis (FSGS); and this variant has been shown to likely increase INF2 interaction with profilin 2 and the F-actin capping protein, resulting in aberrant regulation of actin dynamics (Brown et al. 2010. PubMed ID: 20023659; Rollason et al. 2016. PubMed ID: 26764407). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	.;.;D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.82	T;D;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.3	M;M;M
PhyloP100		1.8
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.051	T;T;D
Sift4G	Benign	0.085	T;T;T
Polyphen		0.98	D;.;D
Vest4		0.54
MutPred		0.73		Gain of catalytic residue at L185 (P = 0);Gain of catalytic residue at L185 (P = 0);Gain of catalytic residue at L185 (P = 0);
MVP		0.95
MPC		2.6
ClinPred		0.72	D
GERP RS		2.0
Varity_R		0.84
gMVP		0.93
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267606877; hg19: chr14-105169680;