NM_014141.6:c.3476-15C>A

Variant names:

• chr7-148383634-C-A
• rs77706740
• NM_014141.6:c.3476-15C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014141.6(CNTNAP2):​c.3476-15C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,613,952 control chromosomes in the GnomAD database, including 943 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (70 hom., cov: 32)
  • Exomes 𝑓: 0.032 (873 hom.)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0980
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-148383634-C-A is Benign according to our data. Variant chr7-148383634-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0251 (3824/152284) while in subpopulation NFE AF = 0.0388 (2641/68018). AF 95% confidence interval is 0.0376. There are 70 homozygotes in GnomAd4. There are 1848 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 70 AR,AD gene

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.3476-15C>A		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.3476-15C>A		intron	N/A	ENSP00000354778.3	Q9UHC6-1
	CNTNAP2	ENST00000463592.3	TSL:1	c.-194-15C>A		intron	N/A	ENSP00000486292.1	Q9UHC6-2
	CNTNAP2	ENST00000628930.2	TSL:2	c.653-15C>A		intron	N/A	ENSP00000487516.1	B7Z1Y6

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3823 AN: 152166 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00767

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0389

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0250 AC: 6288 AN: 251190 AF XY: 0.0255

Gnomad AFR exome AF: 0.00586

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0303

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0346

Gnomad NFE exome AF: 0.0374

Gnomad OTH exome AF: 0.0268

GnomAD4 exome AF: 0.0321 AC: 46868 AN: 1461668 Hom.: 873 Cov.: 33 AF XY: 0.0317 AC XY: 23020 AN XY: 727146

African (AFR) AF: 0.00445 AC: 149 AN: 33478

American (AMR) AF: 0.0135 AC: 604 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0287 AC: 750 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39664

South Asian (SAS) AF: 0.00908 AC: 783 AN: 86254

European-Finnish (FIN) AF: 0.0349 AC: 1862 AN: 53414

Middle Eastern (MID) AF: 0.0147 AC: 85 AN: 5768

European-Non Finnish (NFE) AF: 0.0368 AC: 40913 AN: 1111846

Other (OTH) AF: 0.0285 AC: 1719 AN: 60390

GnomAD4 genome AF: 0.0251 AC: 3824 AN: 152284 Hom.: 70 Cov.: 32 AF XY: 0.0248 AC XY: 1848 AN XY: 74470

African (AFR) AF: 0.00772 AC: 321 AN: 41560

American (AMR) AF: 0.0173 AC: 265 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4828

European-Finnish (FIN) AF: 0.0367 AC: 389 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0388 AC: 2641 AN: 68018

Other (OTH) AF: 0.0345 AC: 73 AN: 2114

Alfa AF: 0.0332 Hom.: 20

Bravo AF: 0.0219

Asia WGS AF: 0.00260 AC: 9 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)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Pitt-Hopkins-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.8
DANN	Benign	0.48
PhyloP100		0.098
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs77706740; hg19: chr7-148080726;