rs3779031

Variant names:

• chr7-148229642-A-G
• rs3779031
• NM_014141.6:c.3248-4A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014141.6(CNTNAP2):​c.3248-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,613,586 control chromosomes in the GnomAD database, including 32,279 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2955 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29324 hom.)
• Consequence: CNTNAP2 NM_014141.6 splice_region, intron
• Scores: Splicing: ADA: 0.00001247
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.39
• Publications: 15 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: Illumina, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 7-148229642-A-G is Benign according to our data. Variant chr7-148229642-A-G is described in ClinVar as Benign. ClinVar VariationId is 95566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.312 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	NM_014141.6	MANE Select	c.3248-4A>G		splice_region intron	N/A	NP_054860.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.3248-4A>G		splice_region intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000628930.2	TSL:2	c.425-4A>G		splice_region intron	N/A	ENSP00000487516.1
	CNTNAP2	ENST00000627772.2	TSL:2	n.1421-4A>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28274 AN: 152048 Hom.: 2943 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.0851

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.218 AC: 54774 AN: 250762 AF XY: 0.212

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.0864

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.194 AC: 283444 AN: 1461420 Hom.: 29324 Cov.: 33 AF XY: 0.193 AC XY: 140190 AN XY: 726998

African (AFR) AF: 0.140 AC: 4680 AN: 33472

American (AMR) AF: 0.349 AC: 15597 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0847 AC: 2214 AN: 26134

East Asian (EAS) AF: 0.312 AC: 12383 AN: 39686

South Asian (SAS) AF: 0.213 AC: 18404 AN: 86246

European-Finnish (FIN) AF: 0.256 AC: 13691 AN: 53382

Middle Eastern (MID) AF: 0.120 AC: 691 AN: 5768

European-Non Finnish (NFE) AF: 0.184 AC: 204489 AN: 1111646

Other (OTH) AF: 0.187 AC: 11295 AN: 60376

GnomAD4 genome AF: 0.186 AC: 28322 AN: 152166 Hom.: 2955 Cov.: 32 AF XY: 0.192 AC XY: 14297 AN XY: 74402

African (AFR) AF: 0.141 AC: 5861 AN: 41510

American (AMR) AF: 0.270 AC: 4128 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0851 AC: 295 AN: 3468

East Asian (EAS) AF: 0.325 AC: 1684 AN: 5180

South Asian (SAS) AF: 0.238 AC: 1149 AN: 4818

European-Finnish (FIN) AF: 0.263 AC: 2791 AN: 10594

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11905 AN: 67982

Other (OTH) AF: 0.186 AC: 392 AN: 2112

Alfa AF: 0.178 Hom.: 5042

Bravo AF: 0.187

Asia WGS AF: 0.277 AC: 963 AN: 3478

EpiCase AF: 0.159

EpiControl AF: 0.162

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Cortical dysplasia-focal epilepsy syndrome (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Pitt-Hopkins-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.015
DANN	Benign	0.39
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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: rs3779031; hg19: chr7-147926734; COSMIC: COSV62158062;