Genetic Variant FMN2:p.Lys420Arg (chr1-240093368-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020066.5(FMN2):c.1259A>G(p.Lys420Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K420T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FMN2
NM_020066.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.42

Publications

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

FMN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13909194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMN2	NM_020066.5 link	c.1259A>G	p.Lys420Arg	missense_variant	Exon 1 of 18	ENST00000319653.14	NP_064450.3	Q9NZ56-1Q9HBL1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMN2	ENST00000319653.14 link	c.1259A>G	p.Lys420Arg	missense_variant	Exon 1 of 18	5	NM_020066.5	ENSP00000318884.9		Q9NZ56-1
FMN2	ENST00000447095.5 link	c.-87+25295A>G		intron_variant	Intron 2 of 6	3		ENSP00000409308.1		B0QZA8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461068

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.00

AC:

AN:

86168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111644

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.20

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.029

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.66

M_CAP

Benign

0.067

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.0

PhyloP100

5.4

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.30

Sift

Benign

0.061

Sift4G

Benign

0.15

Polyphen

0.25

Vest4

0.075

MutPred

0.14

Loss of methylation at K420 (P = 0.007);

MVP

0.83

MPC

0.65

ClinPred

0.77

GERP RS

3.0

Varity_R

0.27

gMVP

0.29

Mutation Taster

=91/9

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over