7-146116828-T-G

Position:

chr7-146116828-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014141.6(CNTNAP2):c.-49T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,432,810 control chromosomes in the GnomAD database, including 35 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 0.0018 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 30 hom. )

Consequence

CNTNAP2
NM_014141.6 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -1.17

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 7-146116828-T-G is Benign according to our data. Variant chr7-146116828-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136837.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00208 (2664/1280540) while in subpopulation SAS AF= 0.0169 (1289/76432). AF 95% confidence interval is 0.0161. There are 30 homozygotes in gnomad4_exome. There are 1633 alleles in male gnomad4_exome subpopulation. Median coverage is 19. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6 linkuse as main transcript	c.-49T>G		5_prime_UTR_variant	1/24	ENST00000361727.8	NP_054860.1	Q9UHC6-1A0A090N7T7B2RCH4
CNTNAP2	XM_017011950.3 linkuse as main transcript	c.-49T>G		5_prime_UTR_variant	1/14		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727 linkuse as main transcript	c.-49T>G		5_prime_UTR_variant	1/24	1	NM_014141.6	ENSP00000354778.3		Q9UHC6-1
CNTNAP2	ENST00000625365 linkuse as main transcript	c.-49T>G		5_prime_UTR_variant	2/4	5		ENSP00000485955.1		A0A0D9SES4

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

278

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00450

AC:

615

AN:

136780

Hom.:

AF XY:

0.00534

AC XY:

396

AN XY:

74200

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.0134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0171

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00138

Gnomad OTH exome

AF:

0.00517

GnomAD4 exome

AF:

0.00208

AC:

2664

AN:

1280540

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

1633

AN XY:

633330

show subpopulations

Gnomad4 AFR exome

AF:

0.000375

Gnomad4 AMR exome

AF:

0.00184

Gnomad4 ASJ exome

AF:

0.0129

Gnomad4 EAS exome

AF:

0.0000286

Gnomad4 SAS exome

AF:

0.0169

Gnomad4 FIN exome

AF:

0.0000978

Gnomad4 NFE exome

AF:

0.000726

Gnomad4 OTH exome

AF:

0.00379

GnomAD4 genome

AF:

0.00183

AC:

278

AN:

152270

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.0150

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0178

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00319

Hom.:

Bravo

AF:

0.00161

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pitt-Hopkins-like syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 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. -

Cortical dysplasia-focal epilepsy syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.6

DANN

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over