rs138477292

chr7-148383806-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014141.6(CNTNAP2):c.3633G>A(p.Glu1211=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 1,614,160 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (81 hom.)
• Consequence: CNTNAP2 NM_014141.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.543

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 7-148383806-G-A is Benign according to our data. Variant chr7-148383806-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148383806-G-A is described in Lovd as [Benign]. Variant chr7-148383806-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.543 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00901 (13176/1461858) while in subpopulation SAS AF= 0.0168 (1451/86254). AF 95% confidence interval is 0.0161. There are 81 homozygotes in gnomad4_exome. There are 6778 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP2	NM_014141.6	c.3633G>A	p.Glu1211=	synonymous_variant	22/24	ENST00000361727.8
LOC105375554	XR_928093.3	n.446-2136C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.3633G>A	p.Glu1211=	synonymous_variant	22/24	1	NM_014141.6	P1

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 974 AN: 152184 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00974

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00791 AC: 1987 AN: 251270 Hom.: 8 AF XY: 0.00896 AC XY: 1217 AN XY: 135876

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0176

Gnomad FIN exome AF: 0.00753

Gnomad NFE exome AF: 0.00994

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00901 AC: 13176 AN: 1461858 Hom.: 81 Cov.: 33 AF XY: 0.00932 AC XY: 6778 AN XY: 727228

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0168

Gnomad4 FIN exome AF: 0.00856

Gnomad4 NFE exome AF: 0.00950

Gnomad4 OTH exome AF: 0.00778

GnomAD4 genome AF: 0.00640 AC: 975 AN: 152302 Hom.: 12 Cov.: 33 AF XY: 0.00620 AC XY: 462 AN XY: 74486

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0161

Gnomad4 FIN AF: 0.00650

Gnomad4 NFE AF: 0.00976

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00844 Hom.: 3

Bravo AF: 0.00551

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.00871

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cortical dysplasia-focal epilepsy syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	5.9
Dann	Benign	0.57

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: rs138477292; hg19: chr7-148080898; COSMIC: COSV105926238;