Genetic Variant NM_020066.5:c.148A>C (chr1-240092257-A-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020066.5(FMN2):c.148A>C(p.Lys50Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000605 in 975,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

FMN2
NM_020066.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.07

Publications

1 publications found

Variant links:

Genes affected

FMN2 (HGNC:14074): (formin 2) This gene is a member of the formin homology protein family. The encoded protein is thought to have essential roles in organization of the actin cytoskeleton and in cell polarity. This protein mediates the formation of an actin mesh that positions the spindle during oogenesis and also regulates the formation of actin filaments in the nucleus. This protein also forms a perinuclear actin/focal-adhesion system that regulates the shape and position of the nucleus during cell migration. Mutations in this gene have been associated with infertility and also with an autosomal recessive form of intellectual disability (MRT47). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jul 2017]

FMN2 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 47
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FMN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.034978926).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020066.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FMN2	NM_020066.5	MANE Select	c.148A>C	p.Lys50Gln	missense	Exon 1 of 18	NP_064450.3
FMN2	NM_001305424.2		c.148A>C	p.Lys50Gln	missense	Exon 1 of 19	NP_001292353.1
FMN2	NM_001348094.2		c.148A>C	p.Lys50Gln	missense	Exon 1 of 15	NP_001335023.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMN2	ENST00000319653.14	TSL:5 MANE Select	c.148A>C	p.Lys50Gln	missense	Exon 1 of 18	ENSP00000318884.9	Q9NZ56-1
	FMN2	ENST00000447095.5	TSL:3	c.-87+24184A>C		intron	N/A	ENSP00000409308.1	B0QZA8

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

97938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00128

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:

0.0000413

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000104

AC:

AN:

144786

AF XY:

0.0000894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000616

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000171

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000513

AC:

AN:

877336

Hom.:

Cov.:

AF XY:

0.0000449

AC XY:

AN XY:

445238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21788

American (AMR)

AF:

0.000467

AC:

AN:

36408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19014

East Asian (EAS)

AF:

0.00

AC:

AN:

33178

South Asian (SAS)

AF:

0.00

AC:

AN:

71852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3856

European-Non Finnish (NFE)

AF:

0.0000458

AC:

AN:

611730

Other (OTH)

AF:

0.00

AC:

AN:

38028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000143

AC:

AN:

97992

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

46788

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24242

American (AMR)

AF:

0.00128

AC:

AN:

9372

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2602

East Asian (EAS)

AF:

0.00

AC:

AN:

3748

South Asian (SAS)

AF:

0.00

AC:

AN:

2524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

186

European-Non Finnish (NFE)

AF:

0.0000413

AC:

AN:

48434

Other (OTH)

AF:

0.00

AC:

AN:

1308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

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:

0.0000623

Hom.:

Bravo

AF:

0.000268

ExAC

AF:

0.0000178

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.22

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.44

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

PhyloP100

4.1

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.3

REVEL

Benign

0.098

Sift

Benign

0.033

Sift4G

Pathogenic

0.0

Polyphen

0.055

Vest4

0.27

MutPred

0.22

Loss of glycosylation at K50 (P = 0.0102)

MVP

0.33

MPC

0.85

ClinPred

0.14

GERP RS

1.6

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.14

gMVP

0.16

Mutation Taster

=92/8

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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