NM_014141.6:c.3716-5_3716-4insGT

Variant names:

• chr7-148409385-C-CTG
• rs60451214
• NM_014141.6:c.3716-5_3716-4insGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_014141.6(CNTNAP2):​c.3716-5_3716-4insGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,581,614 control chromosomes in the GnomAD database, including 254,248 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25617 hom., cov: 33)
  • Exomes 𝑓: 0.56 (228631 hom.)
• Consequence: CNTNAP2 NM_014141.6 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.11
• Publications: 2 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: G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ENSG00000287636 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 7-148409385-C-CTG is Benign according to our data. Variant chr7-148409385-C-CTG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014141.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	NM_014141.6	MANE Select	c.3716-5_3716-4insGT		splice_region intron	N/A	NP_054860.1	A0A090N7T7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.3716-6_3716-5insTG		splice_region intron	N/A	ENSP00000354778.3	Q9UHC6-1
	CNTNAP2	ENST00000463592.3	TSL:1	c.47-6_47-5insTG		splice_region intron	N/A	ENSP00000486292.1	Q9UHC6-2
	CNTNAP2	ENST00000628930.2	TSL:2	c.893-6_893-5insTG		splice_region intron	N/A	ENSP00000487516.1	B7Z1Y6

Frequencies

GnomAD3 genomes AF: 0.574 AC: 86897 AN: 151390 Hom.: 25599 Cov.: 33

Gnomad AFR AF: 0.659

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.536

GnomAD2 exomes AF: 0.389 AC: 62495 AN: 160516 AF XY: 0.401

Gnomad AFR exome AF: 0.501

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.358

Gnomad EAS exome AF: 0.188

Gnomad FIN exome AF: 0.565

Gnomad NFE exome AF: 0.444

Gnomad OTH exome AF: 0.375

GnomAD4 exome AF: 0.559 AC: 799103 AN: 1430106 Hom.: 228631 Cov.: 32 AF XY: 0.561 AC XY: 399680 AN XY: 712872

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.662 AC: 21689 AN: 32774

American (AMR) AF: 0.311 AC: 13872 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 12057 AN: 25896

East Asian (EAS) AF: 0.355 AC: 14017 AN: 39512

South Asian (SAS) AF: 0.616 AC: 52676 AN: 85544

European-Finnish (FIN) AF: 0.652 AC: 34680 AN: 53180

Middle Eastern (MID) AF: 0.473 AC: 2698 AN: 5702

European-Non Finnish (NFE) AF: 0.567 AC: 614844 AN: 1083620

Other (OTH) AF: 0.550 AC: 32570 AN: 59270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.574 AC: 86949 AN: 151508 Hom.: 25617 Cov.: 33 AF XY: 0.570 AC XY: 42227 AN XY: 74046

African (AFR) AF: 0.659 AC: 27222 AN: 41324

American (AMR) AF: 0.393 AC: 5986 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1613 AN: 3454

East Asian (EAS) AF: 0.373 AC: 1922 AN: 5148

South Asian (SAS) AF: 0.619 AC: 2969 AN: 4800

European-Finnish (FIN) AF: 0.656 AC: 6911 AN: 10542

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.571 AC: 38657 AN: 67702

Other (OTH) AF: 0.537 AC: 1128 AN: 2102

Alfa AF: 0.461 Hom.: 1584

Asia WGS AF: 0.516 AC: 1795 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cortical dysplasia-focal epilepsy syndrome (2)
-	-	1	CNTNAP2-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs60451214; hg19: chr7-148106477;