7-146116845-C-T

Position:

• chr7-146116845-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_014141.6(CNTNAP2):​c.-32C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,522,870 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: CNTNAP2 NM_014141.6 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.18

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 7-146116845-C-T is Benign according to our data. Variant chr7-146116845-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136838.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.-32C>T		5_prime_UTR_variant	1/24	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.-32C>T		5_prime_UTR_variant	1/14		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727	c.-32C>T		5_prime_UTR_variant	1/24	1	NM_014141.6	ENSP00000354778.3
CNTNAP2	ENST00000625365	c.-32C>T		5_prime_UTR_variant	2/4	5		ENSP00000485955.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000276 AC: 39 AN: 141452 Hom.: 0 AF XY: 0.000353 AC XY: 27 AN XY: 76522

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00147

Gnomad EAS exome AF: 0.0000923

Gnomad SAS exome AF: 0.00104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.000482

GnomAD4 exome AF: 0.000155 AC: 212 AN: 1370580 Hom.: 1 Cov.: 28 AF XY: 0.000215 AC XY: 145 AN XY: 674340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000283

Gnomad4 ASJ exome AF: 0.00113

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000330

Gnomad4 OTH exome AF: 0.000247

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000855 Hom.: 0

Bravo AF: 0.0000491

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 01, 2014

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	-0.62
CADD	Benign	13
DANN	Benign	0.85

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: rs587780903; hg19: chr7-145813937;