rs4726793

Positions:

• chr7-146579798-G-A
• chr7-146579798-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014141.6(CNTNAP2):​c.98-194473G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 152,098 control chromosomes in the GnomAD database, including 49,760 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 0.80 (49760 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0110

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.98-194473G>A		intron_variant		ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.98-194473G>A		intron_variant			XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.98-194473G>A		intron_variant		1	NM_014141.6	ENSP00000354778	P1
CNTNAP2	ENST00000625365.2	c.98-194473G>A		intron_variant		5		ENSP00000485955
CNTNAP2	ENST00000637150.1	n.27-194473G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122263 AN: 151980 Hom.: 49718 Cov.: 32

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.841

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.795

Gnomad EAS AF: 0.674

Gnomad SAS AF: 0.881

Gnomad FIN AF: 0.850

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.803

Gnomad OTH AF: 0.767

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

GnomAD4 genome AF: 0.804 AC: 122357 AN: 152098 Hom.: 49760 Cov.: 32 AF XY: 0.804 AC XY: 59755 AN XY: 74334

Gnomad4 AFR AF: 0.871

Gnomad4 AMR AF: 0.624

Gnomad4 ASJ AF: 0.795

Gnomad4 EAS AF: 0.675

Gnomad4 SAS AF: 0.881

Gnomad4 FIN AF: 0.850

Gnomad4 NFE AF: 0.803

Gnomad4 OTH AF: 0.769

Alfa AF: 0.778 Hom.: 7027

Bravo AF: 0.787

Asia WGS AF: 0.779 AC: 2710 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.59
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs4726793; hg19: chr7-146276890;