dbSNP rs184709736: INF2:p.Ser293Ser (chr14-104706945-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_022489.4(INF2):c.879G>A(p.Ser293Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,603,198 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S293S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0053 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0071 ( 66 hom. )

Consequence

INF2
NM_022489.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: -1.92

Publications

4 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 14-104706945-G-A is Benign according to our data. Variant chr14-104706945-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261629.

BP7

Synonymous conserved (PhyloP=-1.92 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00532 (809/152182) while in subpopulation AMR AF = 0.0137 (209/15294). AF 95% confidence interval is 0.0121. There are 2 homozygotes in GnomAd4. There are 381 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 809 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022489.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INF2	NM_022489.4	MANE Select	c.879G>A	p.Ser293Ser	synonymous	Exon 7 of 23	NP_071934.3	Q27J81-1
INF2	NM_001426862.1		c.879G>A	p.Ser293Ser	synonymous	Exon 7 of 23	NP_001413791.1
INF2	NM_001426863.1		c.879G>A	p.Ser293Ser	synonymous	Exon 7 of 23	NP_001413792.1	Q27J81-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INF2	ENST00000392634.9	TSL:5 MANE Select	c.879G>A	p.Ser293Ser	synonymous	Exon 7 of 23	ENSP00000376410.4	Q27J81-1
INF2	ENST00000617571.5	TSL:1	n.879G>A		non_coding_transcript_exon	Exon 6 of 22	ENSP00000483829.2	A0A087X118
INF2	ENST00000675207.1		c.975G>A	p.Ser325Ser	synonymous	Exon 7 of 23	ENSP00000502644.1	A0A6Q8PHA2

Frequencies

GnomAD3 genomes

AF:

0.00533

AC:

810

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00225

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00674

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00777

AC:

1792

AN:

230564

AF XY:

0.00707

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.0254

Gnomad ASJ exome

AF:

0.00496

Gnomad EAS exome

AF:

0.000169

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00657

Gnomad OTH exome

AF:

0.00575

GnomAD4 exome

AF:

0.00706

AC:

10244

AN:

1451016

Hom.:

Cov.:

AF XY:

0.00686

AC XY:

4956

AN XY:

722164

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33446

American (AMR)

AF:

0.0241

AC:

1074

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.00426

AC:

111

AN:

26034

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39676

South Asian (SAS)

AF:

0.00396

AC:

341

AN:

86106

European-Finnish (FIN)

AF:

0.00216

AC:

AN:

43954

Middle Eastern (MID)

AF:

0.00705

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00729

AC:

8098

AN:

1111332

Other (OTH)

AF:

0.00711

AC:

428

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

574

1147

1721

2294

2868

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

324

648

972

1296

1620

<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:

0.00532

AC:

809

AN:

152182

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

381

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41500

American (AMR)

AF:

0.0137

AC:

209

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00394

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00674

AC:

458

AN:

67986

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

133

177

221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00671

Hom.:

Bravo

AF:

0.00667

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00594

EpiControl

AF:

0.00607

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E (2)

Focal segmental glomerulosclerosis 5 (1)

Inborn genetic diseases (1)

Kidney disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.046

(source)

DANN

Benign

0.90

PhyloP100

-1.9

PromoterAI

0.0031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over