7-146116732-G-C

Variant names:

• chr7-146116732-G-C
• rs769212821
• ENST00000625365.2:c.-145G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000625365.2(CNTNAP2):​c.-145G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000635 in 625,024 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (1 hom.)
• Consequence: CNTNAP2 ENST00000625365.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.415
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.-145G>C		upstream_gene_variant		ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.-145G>C		upstream_gene_variant			XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000625365.2	c.-145G>C		5_prime_UTR_variant	Exon 2 of 4	5		ENSP00000485955.1
CNTNAP2	ENST00000361727.8	c.-145G>C		upstream_gene_variant		1	NM_014141.6	ENSP00000354778.3
CNTNAP2	ENST00000637150.1	n.-216G>C		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000649 AC: 307 AN: 472932 Hom.: 1 Cov.: 5 AF XY: 0.000579 AC XY: 143 AN XY: 247166

African (AFR) AF: 0.000385 AC: 5 AN: 12994

American (AMR) AF: 0.00130 AC: 25 AN: 19224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13860

East Asian (EAS) AF: 0.00 AC: 0 AN: 31076

South Asian (SAS) AF: 0.00 AC: 0 AN: 46166

European-Finnish (FIN) AF: 0.000101 AC: 3 AN: 29562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1994

European-Non Finnish (NFE) AF: 0.000882 AC: 257 AN: 291278

Other (OTH) AF: 0.000635 AC: 17 AN: 26778

GnomAD4 genome AF: 0.000592 AC: 90 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.000525 AC XY: 39 AN XY: 74296

African (AFR) AF: 0.000193 AC: 8 AN: 41444

American (AMR) AF: 0.00111 AC: 17 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68002

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000703

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pitt-Hopkins-like syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.86
PhyloP100		-0.41
PromoterAI		-0.085	Neutral
Mutation Taster		=250/50	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs769212821; hg19: chr7-145813824;