NM_005249.5:c.256C>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BS2BP4

This summary comes from the ClinGen Evidence Repository: The p.Gln86Lys variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Gln86Lys variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Gln86Lys variant in FOXG1 is absent from gnomAD (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Rett/Angelman-like expert panel: BS2, BP4 (approved 8/25/22). LINK:https://erepo.genome.network/evrepo/ui/classification/CA222854/MONDO:0100040/016

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

FOXG1
NM_005249.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:3

Conservation

PhyloP100: 1.66

Publications

6 publications found

Variant links:

Genes affected

FOXG1 (HGNC:3811): (forkhead box G1) This locus encodes a member of the fork-head transcription factor family. The encoded protein, which functions as a transcriptional repressor, is highly expressed in neural tissues during brain development. Mutations at this locus have been associated with Rett syndrome and a diverse spectrum of neurodevelopmental disorders defined as part of the FOXG1 syndrome. This gene is disregulated in many types of cancer and is the target of multiple microRNAs that regulate the proliferation of tumor cells. [provided by RefSeq, Jul 2020]

FOXG1 links:

LINC01551 (HGNC:19828): (long intergenic non-protein coding RNA 1551)

LINC01551 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5 link	c.256C>A	p.Gln86Lys	missense_variant	Exon 1 of 1	ENST00000313071.7	NP_005240.3	P55316

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXG1	ENST00000313071.7 link	c.256C>A	p.Gln86Lys	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3	P55316
FOXG1	ENST00000706482.1 link	c.256C>A	p.Gln86Lys	missense_variant	Exon 2 of 2			ENSP00000516406.1	P55316
LINC01551	ENST00000675861.1 link	n.374+1522C>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00000678

AC:

AN:

147538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000107

AC:

AN:

934236

Hom.:

Cov.:

AF XY:

0.00000227

AC XY:

AN XY:

439890

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18282

American (AMR)

AF:

0.00

AC:

AN:

4584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8942

East Asian (EAS)

AF:

0.00

AC:

AN:

13432

South Asian (SAS)

AF:

0.00

AC:

AN:

18162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2202

European-Non Finnish (NFE)

AF:

0.00000122

AC:

AN:

821688

Other (OTH)

AF:

0.00

AC:

AN:

34020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.00000678

AC:

AN:

147538

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71806

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40926

American (AMR)

AF:

0.00

AC:

AN:

14828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3398

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66354

Other (OTH)

AF:

0.00

AC:

AN:

2026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 13, 2012

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 14, 2025

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. -

FOXG1 disorder

Benign:1

Sep 01, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The p.Gln86Lys variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Gln86Lys variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Gln86Lys variant in FOXG1 is absent from gnomAD (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Rett/Angelman-like expert panel: BS2, BP4 (approved 8/25/22). -

Rett syndrome, congenital variant

Benign:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.31

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.49

M_CAP

Benign

0.035

MetaRNN

Benign

0.071

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.7

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.22

REVEL

Benign

0.029

Sift

Benign

0.11

Sift4G

Benign

0.69

Polyphen

0.019

Vest4

0.10

MutPred

0.31

Gain of catalytic residue at P84 (P = 0.001);

MVP

0.18

ClinPred

0.088

GERP RS

2.0

Varity_R

0.14

gMVP

0.20

Mutation Taster

=97/3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over