7-147395523-C-T

Variant names:

• chr7-147395523-C-T
• rs700308
• NM_014141.6:c.1499-86C>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.1499-86C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,298,102 control chromosomes in the GnomAD database, including 14,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1523 hom., cov: 32)
  • Exomes 𝑓: 0.14 (12892 hom.)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.198
• Publications: 4 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=-0.81).
• BP6: Variant 7-147395523-C-T is Benign according to our data. Variant chr7-147395523-C-T is described in ClinVar as Benign. ClinVar VariationId is 670795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1499-86C>T		intron_variant	Intron 9 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1499-86C>T		intron_variant	Intron 9 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1499-86C>T		intron_variant	Intron 9 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19601 AN: 151892 Hom.: 1520 Cov.: 32

Gnomad AFR AF: 0.0753

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.139 AC: 159787 AN: 1146092 Hom.: 12892 AF XY: 0.140 AC XY: 81978 AN XY: 584200

African (AFR) AF: 0.0731 AC: 1983 AN: 27136

American (AMR) AF: 0.232 AC: 10117 AN: 43670

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3065 AN: 23498

East Asian (EAS) AF: 0.353 AC: 13336 AN: 37814

South Asian (SAS) AF: 0.173 AC: 13612 AN: 78668

European-Finnish (FIN) AF: 0.165 AC: 8462 AN: 51138

Middle Eastern (MID) AF: 0.209 AC: 1053 AN: 5036

European-Non Finnish (NFE) AF: 0.122 AC: 101041 AN: 829374

Other (OTH) AF: 0.143 AC: 7118 AN: 49758

GnomAD4 genome AF: 0.129 AC: 19619 AN: 152010 Hom.: 1523 Cov.: 32 AF XY: 0.134 AC XY: 9954 AN XY: 74308

African (AFR) AF: 0.0755 AC: 3134 AN: 41522

American (AMR) AF: 0.190 AC: 2895 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3464

East Asian (EAS) AF: 0.317 AC: 1634 AN: 5150

South Asian (SAS) AF: 0.172 AC: 829 AN: 4826

European-Finnish (FIN) AF: 0.160 AC: 1695 AN: 10580

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8510 AN: 67924

Other (OTH) AF: 0.141 AC: 297 AN: 2104

Alfa AF: 0.122 Hom.: 193

Bravo AF: 0.129

Asia WGS AF: 0.231 AC: 799 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	-0.81
CADD	Benign	5.8
DANN	Benign	0.49
PhyloP100		0.20
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: rs700308; hg19: chr7-147092615; COSMIC: COSV62186420;