rs12703926

Variant names:

• chr7-147537635-G-A
• rs12703926
• NM_014141.6:c.1778-24503G>A

Variant summary

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

The NM_014141.6(CNTNAP2):​c.1778-24503G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 151,872 control chromosomes in the GnomAD database, including 3,326 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 0.19 (3326 hom., cov: 33)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.465

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=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1778-24503G>A		intron_variant	Intron 11 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1778-24503G>A		intron_variant	Intron 11 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1778-24503G>A		intron_variant	Intron 11 of 23	1	NM_014141.6	ENSP00000354778.3
CNTNAP2	ENST00000636870.1	n.1640-24503G>A		intron_variant	Intron 9 of 21	5
CNTNAP2	ENST00000637825.1	n.1261-24503G>A		intron_variant	Intron 8 of 13	5
CNTNAP2	ENST00000638117.1	n.1681-24503G>A		intron_variant	Intron 10 of 12	5

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29020 AN: 151756 Hom.: 3322 Cov.: 33

Gnomad AFR AF: 0.0659

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.190

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

GnomAD4 genome AF: 0.191 AC: 29029 AN: 151872 Hom.: 3326 Cov.: 33 AF XY: 0.190 AC XY: 14065 AN XY: 74204

Gnomad4 AFR AF: 0.0658

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.288

Gnomad4 FIN AF: 0.242

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.194

Alfa AF: 0.239 Hom.: 6823

Bravo AF: 0.177

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.2
DANN	Benign	0.40

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: rs12703926; hg19: chr7-147234727;