7-146655484-C-T

Variant names:

• chr7-146655484-C-T
• rs10277654
• NM_014141.6:c.98-118787C>T

Variant summary

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

The NM_014141.6(CNTNAP2):​c.98-118787C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 149,634 control chromosomes in the GnomAD database, including 17,487 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 0.47 (17487 hom., cov: 28)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97
• Publications: 3 publications found

Genes affected

CNTNAP2 (HGNC:13830): (contactin associated protein 2) This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal growth factor repeats and laminin G domains. In addition, it includes an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, thrombospondin N-terminal-like domains and a putative PDZ binding site. This protein is localized at the juxtaparanodes of myelinated axons, and mediates interactions between neurons and glia during nervous system development and is also involved in localization of potassium channels within differentiating axons. This gene encompasses almost 1.5% of chromosome 7 and is one of the largest genes in the human genome. It is directly bound and regulated by forkhead box protein P2, a transcription factor related to speech and language development. This gene has been implicated in multiple neurodevelopmental disorders, including Gilles de la Tourette syndrome, schizophrenia, epilepsy, autism, ADHD and intellectual disability. [provided by RefSeq, Jul 2017]

CNTNAP2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE, NO_KNOWN Submitted by: ClinGen
• cortical dysplasia-focal epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.98-118787C>T		intron_variant	Intron 1 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.98-118787C>T		intron_variant	Intron 1 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.98-118787C>T		intron_variant	Intron 1 of 23	1	NM_014141.6	ENSP00000354778.3
CNTNAP2	ENST00000625365.2	c.98-118787C>T		intron_variant	Intron 2 of 3	5		ENSP00000485955.1
CNTNAP2	ENST00000637150.1	n.27-118787C>T		intron_variant	Intron 1 of 8	5

Frequencies

GnomAD3 genomes AF: 0.473 AC: 70724 AN: 149544 Hom.: 17482 Cov.: 28

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.458

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

GnomAD4 genome AF: 0.473 AC: 70748 AN: 149634 Hom.: 17487 Cov.: 28 AF XY: 0.469 AC XY: 34164 AN XY: 72834

African (AFR) AF: 0.370 AC: 15041 AN: 40602

American (AMR) AF: 0.382 AC: 5699 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1945 AN: 3466

East Asian (EAS) AF: 0.178 AC: 895 AN: 5040

South Asian (SAS) AF: 0.576 AC: 2740 AN: 4760

European-Finnish (FIN) AF: 0.518 AC: 5106 AN: 9850

Middle Eastern (MID) AF: 0.475 AC: 134 AN: 282

European-Non Finnish (NFE) AF: 0.557 AC: 37692 AN: 67724

Other (OTH) AF: 0.462 AC: 961 AN: 2082

Alfa AF: 0.505 Hom.: 2400

Bravo AF: 0.453

Asia WGS AF: 0.392 AC: 1366 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.22
DANN	Benign	0.38
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: rs10277654; hg19: chr7-146352576;