rs11975946

Positions:

• chr7-147614261-A-G

Variant summary

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

The NM_014141.6(CNTNAP2):​c.1898-24845A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 151,862 control chromosomes in the GnomAD database, including 12,231 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 0.40 (12231 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0950

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=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1898-24845A>G		intron_variant		ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1898-24845A>G		intron_variant			XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1898-24845A>G		intron_variant		1	NM_014141.6	ENSP00000354778	P1
CNTNAP2	ENST00000636870.1	n.1760-24845A>G		intron_variant, non_coding_transcript_variant		5
CNTNAP2	ENST00000637825.1	n.1381-24845A>G		intron_variant, non_coding_transcript_variant		5
CNTNAP2	ENST00000638117.1	n.1801-24845A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60816 AN: 151744 Hom.: 12226 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.382

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

GnomAD4 genome AF: 0.401 AC: 60847 AN: 151862 Hom.: 12231 Cov.: 32 AF XY: 0.400 AC XY: 29682 AN XY: 74228

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.444

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.341

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.386

Alfa AF: 0.414 Hom.: 16415

Bravo AF: 0.398

Asia WGS AF: 0.386 AC: 1339 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.6
DANN	Benign	0.80

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: rs11975946; hg19: chr7-147311353;