rs2074714

Variant names:

• chr7-147562346-A-G
• rs2074714
• NM_014141.6:c.1897+89A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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 -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 VariationId 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 rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1897+89A>G		intron_variant	Intron 12 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1897+89A>G		intron_variant	Intron 12 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1897+89A>G		intron_variant	Intron 12 of 23	1	NM_014141.6	ENSP00000354778.3
CNTNAP2	ENST00000636870.1	n.1759+89A>G		intron_variant	Intron 10 of 21	5
CNTNAP2	ENST00000637825.1	n.1380+89A>G		intron_variant	Intron 9 of 13	5
CNTNAP2	ENST00000638117.1	n.1800+89A>G		intron_variant	Intron 11 of 12	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

African (AFR) AF: 0.730 AC: 23288 AN: 31900

American (AMR) AF: 0.726 AC: 32243 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 16210 AN: 25616

East Asian (EAS) AF: 0.609 AC: 23860 AN: 39160

South Asian (SAS) AF: 0.620 AC: 52113 AN: 84114

European-Finnish (FIN) AF: 0.611 AC: 30391 AN: 49778

Middle Eastern (MID) AF: 0.630 AC: 2552 AN: 4048

European-Non Finnish (NFE) AF: 0.658 AC: 691274 AN: 1050430

Other (OTH) AF: 0.661 AC: 38253 AN: 57858

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

African (AFR) AF: 0.729 AC: 30251 AN: 41500

American (AMR) AF: 0.718 AC: 10975 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2147 AN: 3472

East Asian (EAS) AF: 0.626 AC: 3237 AN: 5168

South Asian (SAS) AF: 0.630 AC: 3038 AN: 4822

European-Finnish (FIN) AF: 0.594 AC: 6266 AN: 10556

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.656 AC: 44599 AN: 67986

Other (OTH) AF: 0.673 AC: 1421 AN: 2112

Alfa AF: 0.669 Hom.: 5802

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.46
DANN	Benign	0.53
PhyloP100		-1.6
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: rs2074714; hg19: chr7-147259438; COSMIC: COSV62146583;