7-114323014-T-C

Variant names:

• chr7-114323014-T-C
• rs2396722
• ENST00000440349.5:n.-11+34905T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000440349.5(FOXP2):​n.-11+34905T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 151,934 control chromosomes in the GnomAD database, including 15,704 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (15704 hom., cov: 32)
• Consequence: FOXP2 ENST00000440349.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.583
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NR_033766.2	n.376+34905T>C		intron_variant	Intron 2 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000440349.5	n.-11+34905T>C		intron_variant	Intron 3 of 11	1		ENSP00000395552.1
FOXP2	ENST00000703616.1	c.-11+34905T>C		intron_variant	Intron 3 of 20			ENSP00000515400.1
FOXP2	ENST00000703613.1	c.-11+34905T>C		intron_variant	Intron 4 of 20			ENSP00000515397.1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67888 AN: 151816 Hom.: 15689 Cov.: 32

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.413

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.447 AC: 67935 AN: 151934 Hom.: 15704 Cov.: 32 AF XY: 0.447 AC XY: 33166 AN XY: 74248

African (AFR) AF: 0.554 AC: 22968 AN: 41426

American (AMR) AF: 0.377 AC: 5754 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 989 AN: 3466

East Asian (EAS) AF: 0.499 AC: 2576 AN: 5164

South Asian (SAS) AF: 0.404 AC: 1944 AN: 4812

European-Finnish (FIN) AF: 0.460 AC: 4853 AN: 10542

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.406 AC: 27580 AN: 67942

Other (OTH) AF: 0.411 AC: 868 AN: 2110

Alfa AF: 0.418 Hom.: 2255

Bravo AF: 0.447

Asia WGS AF: 0.427 AC: 1482 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.4
DANN	Benign	0.69
PhyloP100		0.58
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2396722; hg19: chr7-113963069;