rs6966051

Variant names:

• chr7-114656049-C-T
• rs6966051
• NM_014491.4:c.1267-2017C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_014491.4(FOXP2):​c.1267-2017C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.099 in 152,112 control chromosomes in the GnomAD database, including 1,491 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 0.099 (1491 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000303050 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	NM_014491.4	MANE Select	c.1267-2017C>T		intron	N/A	NP_055306.1	O15409-1
	FOXP2	NM_148898.4		c.1342-2017C>T		intron	N/A	NP_683696.2	O15409-4
	FOXP2	NM_148900.4		c.1318-2017C>T		intron	N/A	NP_683698.2	O15409-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	ENST00000350908.9	TSL:1 MANE Select	c.1267-2017C>T		intron	N/A	ENSP00000265436.7	O15409-1
	FOXP2	ENST00000408937.7	TSL:1	c.1342-2017C>T		intron	N/A	ENSP00000386200.3	O15409-4
	FOXP2	ENST00000393489.8	TSL:1	n.*1061-2017C>T		intron	N/A	ENSP00000377129.4	O15409-8

Frequencies

GnomAD3 genomes AF: 0.0990 AC: 15047 AN: 151992 Hom.: 1497 Cov.: 32

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0658

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.00924

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.107

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

GnomAD4 genome AF: 0.0990 AC: 15056 AN: 152112 Hom.: 1491 Cov.: 32 AF XY: 0.0962 AC XY: 7153 AN XY: 74370

African (AFR) AF: 0.260 AC: 10781 AN: 41446

American (AMR) AF: 0.0657 AC: 1003 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.00913 AC: 44 AN: 4820

European-Finnish (FIN) AF: 0.00924 AC: 98 AN: 10606

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.0378 AC: 2572 AN: 68000

Other (OTH) AF: 0.106 AC: 224 AN: 2108

Alfa AF: 0.0727 Hom.: 927

Bravo AF: 0.109

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.83
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6966051; hg19: chr7-114296104;