dbSNP rs371991103: INF2:c.1736-6C>T (chr14-104708430-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022489.4(INF2):c.1736-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,611,500 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

INF2
NM_022489.4 splice_region, intron

Scores

Splicing: ADA: 0.0002739

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0430

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: 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 14-104708430-C-T is Benign according to our data. Variant chr14-104708430-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 472838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000171 (26/152296) while in subpopulation NFE AF = 0.000323 (22/68012). AF 95% confidence interval is 0.000218. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 26 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	Effect	Exon Rank	Protein	UniProt
INF2	NM_022489.4	MANE Select	c.1736-6C>T	splice_region intron	N/A	NP_071934.3	Q27J81-1
INF2	NM_001426862.1		c.1736-6C>T	splice_region intron	N/A	NP_001413791.1
INF2	NM_001426863.1		c.1736-6C>T	splice_region intron	N/A	NP_001413792.1	Q27J81-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
INF2	ENST00000392634.9	TSL:5 MANE Select	c.1736-6C>T	splice_region intron	N/A	ENSP00000376410.4	Q27J81-1
INF2	ENST00000617571.5	TSL:1	n.1736-6C>T	splice_region intron	N/A	ENSP00000483829.2	A0A087X118
INF2	ENST00000675207.1		c.1832-6C>T	splice_region intron	N/A	ENSP00000502644.1	A0A6Q8PHA2

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000341

AC:

AN:

246328

AF XY:

0.000387

show subpopulations

Gnomad AFR exome

AF:

0.0000657

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000568

Gnomad OTH exome

AF:

0.00100

GnomAD4 exome

AF:

0.000203

AC:

296

AN:

1459204

Hom.:

Cov.:

AF XY:

0.000247

AC XY:

179

AN XY:

725876

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33438

American (AMR)

AF:

0.000134

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.000302

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51990

Middle Eastern (MID)

AF:

0.00254

AC:

AN:

5118

European-Non Finnish (NFE)

AF:

0.000212

AC:

236

AN:

1111688

Other (OTH)

AF:

0.000216

AC:

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.000171

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41556

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000427

Hom.:

Bravo

AF:

0.000196

EpiCase

AF:

0.000982

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

0.043

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00027

dbscSNV1_RF

Benign

0.018

SpliceAI score (max)

0.15

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