chr7-146116731-G-T

Variant names:

• chr7-146116731-G-T
• rs886062045
• ENST00000625365.2:c.-146G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000625365.2(CNTNAP2):​c.-146G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 470,484 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CNTNAP2 ENST00000625365.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.-146G>T		upstream_gene_variant		ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.-146G>T		upstream_gene_variant			XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000625365.2	c.-146G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 4	5		ENSP00000485955.1
CNTNAP2	ENST00000625365.2	c.-146G>T		5_prime_UTR_variant	Exon 2 of 4	5		ENSP00000485955.1
CNTNAP2	ENST00000361727.8	c.-146G>T		upstream_gene_variant		1	NM_014141.6	ENSP00000354778.3
CNTNAP2	ENST00000637150.1	n.-217G>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000213 AC: 1 AN: 470484 Hom.: 0 Cov.: 5 AF XY: 0.00000407 AC XY: 1 AN XY: 245908

African (AFR) AF: 0.00 AC: 0 AN: 12930

American (AMR) AF: 0.00 AC: 0 AN: 19160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13818

East Asian (EAS) AF: 0.00 AC: 0 AN: 31002

South Asian (SAS) AF: 0.0000218 AC: 1 AN: 45942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1988

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 289542

Other (OTH) AF: 0.00 AC: 0 AN: 26624

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		1.9
PromoterAI		-0.097	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs886062045; hg19: chr7-145813823;