rs2074714

Positions:

• chr7-147562346-A-G
• chr7-147562346-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014141.6(CNTNAP2):​c.1897+89A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.658 in 1,539,444 control chromosomes in the GnomAD database, including 334,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (34895 hom., cov: 33)
  • Exomes 𝑓: 0.66 (299705 hom.)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.57

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-147562346-A-G is Benign according to our data. Variant chr7-147562346-A-G is described in ClinVar as [Benign]. Clinvar id is 670633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1897+89A>G		intron_variant		ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1897+89A>G		intron_variant			XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1897+89A>G		intron_variant		1	NM_014141.6	ENSP00000354778	P1
CNTNAP2	ENST00000636870.1	n.1759+89A>G		intron_variant, non_coding_transcript_variant		5
CNTNAP2	ENST00000637825.1	n.1380+89A>G		intron_variant, non_coding_transcript_variant		5
CNTNAP2	ENST00000638117.1	n.1800+89A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102669 AN: 151992 Hom.: 34852 Cov.: 33

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.712

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.630

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.673

GnomAD4 exome AF: 0.656 AC: 910184 AN: 1387334 Hom.: 299705 AF XY: 0.653 AC XY: 453692 AN XY: 694412

Gnomad4 AFR exome AF: 0.730

Gnomad4 AMR exome AF: 0.726

Gnomad4 ASJ exome AF: 0.633

Gnomad4 EAS exome AF: 0.609

Gnomad4 SAS exome AF: 0.620

Gnomad4 FIN exome AF: 0.611

Gnomad4 NFE exome AF: 0.658

Gnomad4 OTH exome AF: 0.661

GnomAD4 genome AF: 0.676 AC: 102765 AN: 152110 Hom.: 34895 Cov.: 33 AF XY: 0.671 AC XY: 49852 AN XY: 74342

Gnomad4 AFR AF: 0.729

Gnomad4 AMR AF: 0.718

Gnomad4 ASJ AF: 0.618

Gnomad4 EAS AF: 0.626

Gnomad4 SAS AF: 0.630

Gnomad4 FIN AF: 0.594

Gnomad4 NFE AF: 0.656

Gnomad4 OTH AF: 0.673

Alfa AF: 0.668 Hom.: 5610

Bravo AF: 0.688

Asia WGS AF: 0.637 AC: 2218 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.46
DANN	Benign	0.53

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: rs2074714; hg19: chr7-147259438; COSMIC: COSV62146583;