7-148420550-C-T

Position:

• chr7-148420550-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014141.6(CNTNAP2):​c.*4934C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 152,050 control chromosomes in the GnomAD database, including 11,347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (11347 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNTNAP2 NM_014141.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.905

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]

LOC105375554 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 7-148420550-C-T is Benign according to our data. Variant chr7-148420550-C-T is described in ClinVar as [Benign]. Clinvar id is 359273.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP2	NM_014141.6	c.*4934C>T		3_prime_UTR_variant	24/24	ENST00000361727.8
LOC105375554	XR_928094.2	n.209+16009G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.*4934C>T		3_prime_UTR_variant	24/24	1	NM_014141.6	P1
CNTNAP2	ENST00000463592.3	c.*4934C>T		3_prime_UTR_variant	4/4	1
CNTNAP2	ENST00000636242.1	n.5731C>T		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53305 AN: 151930 Hom.: 11338 Cov.: 33

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.384

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 FIN exome AF: 0.00

GnomAD4 genome AF: 0.351 AC: 53320 AN: 152050 Hom.: 11347 Cov.: 33 AF XY: 0.356 AC XY: 26447 AN XY: 74332

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.479

Gnomad4 EAS AF: 0.680

Gnomad4 SAS AF: 0.385

Gnomad4 FIN AF: 0.333

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.384

Alfa AF: 0.411 Hom.: 10068

Bravo AF: 0.365

Asia WGS AF: 0.472 AC: 1641 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

Pitt-Hopkins-like syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.8
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs2530310; hg19: chr7-148117642; COSMIC: COSV62186810; COSMIC: COSV62186810;