14-104709371-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_022489.4(INF2):c.2040C>T(p.Pro680Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000856 in 1,612,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

INF2
NM_022489.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.54

Publications

0 publications found

Variant links:

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

INF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 14-104709371-C-T is Benign according to our data. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104709371-C-T is described in CliVar as Likely_benign. Clinvar id is 540070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.54 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000918 (134/1460194) while in subpopulation NFE AF = 0.000119 (132/1111390). AF 95% confidence interval is 0.000102. There are 0 homozygotes in GnomAdExome4. There are 60 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INF2	NM_022489.4 link	c.2040C>T	p.Pro680Pro	synonymous_variant	Exon 11 of 23	ENST00000392634.9	NP_071934.3	Q27J81-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9 link	c.2040C>T	p.Pro680Pro	synonymous_variant	Exon 11 of 23	5	NM_022489.4	ENSP00000376410.4		Q27J81-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000323

AC:

AN:

247982

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000624

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000918

AC:

134

AN:

1460194

Hom.:

Cov.:

AF XY:

0.0000826

AC XY:

AN XY:

726430

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000119

AC:

132

AN:

1111390

Other (OTH)

AF:

0.0000166

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000773

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E

Benign:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 11, 2019

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

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.34

(source)

DANN

Benign

0.70

PhyloP100

-3.5

PromoterAI

-0.0030

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over