rs10255169

Variant names:

• chr7-146321428-G-C
• rs10255169
• NM_014141.6:c.97+204455G>C

Variant summary

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

The NM_014141.6(CNTNAP2):​c.97+204455G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 152,128 control chromosomes in the GnomAD database, including 12,790 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 0.26 (12790 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.954
• Publications: 5 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014141.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	NM_014141.6	MANE Select	c.97+204455G>C		intron	N/A	NP_054860.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.97+204455G>C		intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000625365.2	TSL:5	c.97+204455G>C		intron	N/A	ENSP00000485955.1
	CNTNAP2	ENST00000637150.1	TSL:5	n.26+204455G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40064 AN: 152010 Hom.: 12728 Cov.: 32

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0479

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.0632

Gnomad OTH AF: 0.227

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

GnomAD4 genome AF: 0.264 AC: 40174 AN: 152128 Hom.: 12790 Cov.: 32 AF XY: 0.256 AC XY: 19055 AN XY: 74380

African (AFR) AF: 0.765 AC: 31724 AN: 41462

American (AMR) AF: 0.123 AC: 1880 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 354 AN: 3468

East Asian (EAS) AF: 0.0480 AC: 248 AN: 5170

South Asian (SAS) AF: 0.135 AC: 650 AN: 4816

European-Finnish (FIN) AF: 0.0395 AC: 419 AN: 10618

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.0632 AC: 4297 AN: 67998

Other (OTH) AF: 0.226 AC: 478 AN: 2112

Alfa AF: 0.181 Hom.: 964

Bravo AF: 0.292

Asia WGS AF: 0.144 AC: 502 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.63
DANN	Benign	0.42
PhyloP100		-0.95
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: rs10255169; hg19: chr7-146018520;