Genetic Variant FOXP2:p.Gln166_Gln169dup (chr7-114629882-G-GCAGCAGCAACAA) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_014491.4(FOXP2):c.495_506dupACAACAGCAGCA(p.Gln166_Gln169dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000365 in 1,611,820 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

FOXP2
NM_014491.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 5.77

Publications

0 publications found

Variant links:

Genes affected

FOXP2 (HGNC:13875): (forkhead box P2) This gene encodes a member of the forkhead/winged-helix (FOX) family of transcription factors. It is expressed in fetal and adult brain as well as in several other organs such as the lung and gut. The protein product contains a FOX DNA-binding domain and a large polyglutamine tract and is an evolutionarily conserved transcription factor, which may bind directly to approximately 300 to 400 gene promoters in the human genome to regulate the expression of a variety of genes. This gene is required for proper development of speech and language regions of the brain during embryogenesis, and may be involved in a variety of biological pathways and cascades that may ultimately influence language development. Mutations in this gene cause speech-language disorder 1 (SPCH1), also known as autosomal dominant speech and language disorder with orofacial dyspraxia. Multiple alternative transcripts encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

FOXP2 Gene-Disease associations (from GenCC):

specific language disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
childhood apraxia of speech
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

FOXP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_014491.4

BP6

Variant 7-114629882-G-GCAGCAGCAACAA is Benign according to our data. Variant chr7-114629882-G-GCAGCAGCAACAA is described in ClinVar as Likely_benign. ClinVar VariationId is 242948.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 = 0.000371 (56/150754) while in subpopulation NFE AF = 0.000459 (31/67570). AF 95% confidence interval is 0.000332. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 56 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014491.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FOXP2	NM_014491.4	MANE Select	c.495_506dupACAACAGCAGCA	p.Gln166_Gln169dup	disruptive_inframe_insertion	Exon 5 of 17	NP_055306.1
FOXP2	NM_148898.4		c.570_581dupACAACAGCAGCA	p.Gln191_Gln194dup	disruptive_inframe_insertion	Exon 6 of 18	NP_683696.2
FOXP2	NM_148900.4		c.546_557dupACAACAGCAGCA	p.Gln183_Gln186dup	disruptive_inframe_insertion	Exon 6 of 18	NP_683698.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FOXP2	ENST00000350908.9	TSL:1 MANE Select	c.495_506dupACAACAGCAGCA	p.Gln166_Gln169dup	disruptive_inframe_insertion	Exon 5 of 17	ENSP00000265436.7
FOXP2	ENST00000408937.7	TSL:1	c.570_581dupACAACAGCAGCA	p.Gln191_Gln194dup	disruptive_inframe_insertion	Exon 6 of 18	ENSP00000386200.3
FOXP2	ENST00000390668.3	TSL:1	c.567_578dupACAACAGCAGCA	p.Gln190_Gln193dup	disruptive_inframe_insertion	Exon 5 of 10	ENSP00000375084.3

Frequencies

GnomAD3 genomes

AF:

0.000372

AC:

AN:

150636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00463

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000424

Gnomad FIN

AF:

0.0000953

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000459

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000359

AC:

AN:

247926

AF XY:

0.000350

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00310

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000929

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.000987

GnomAD4 exome

AF:

0.000365

AC:

533

AN:

1461066

Hom.:

Cov.:

AF XY:

0.000367

AC XY:

267

AN XY:

726824

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33472

American (AMR)

AF:

0.000179

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00533

AC:

139

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.0000929

AC:

AN:

86112

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000291

AC:

324

AN:

1111694

Other (OTH)

AF:

0.000646

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000371

AC:

AN:

150754

Hom.:

Cov.:

AF XY:

0.000462

AC XY:

AN XY:

73588

show subpopulations

African (AFR)

AF:

0.000146

AC:

AN:

41066

American (AMR)

AF:

0.00

AC:

AN:

15104

Ashkenazi Jewish (ASJ)

AF:

0.00463

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5068

South Asian (SAS)

AF:

0.000424

AC:

AN:

4718

European-Finnish (FIN)

AF:

0.0000953

AC:

AN:

10492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000459

AC:

AN:

67570

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000988

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Childhood apraxia of speech (2)

FOXP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.8

Mutation Taster

=66/34

polymorphism

(source)

Splicing

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