rs2286127

Variant names:

• chr7-147486051-A-G
• rs2286127
• NM_014141.6:c.1777+10A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-147486051-A-G
• chr7-147486051-A-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_014141.6(CNTNAP2):​c.1777+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,605,856 control chromosomes in the GnomAD database, including 32,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3603 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28643 hom.)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.866
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 7-147486051-A-G is Benign according to our data. Variant chr7-147486051-A-G is described in ClinVar as Benign. ClinVar VariationId is 95559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 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.1777+10A>G		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.1777+10A>G		intron	N/A	ENSP00000354778.3	Q9UHC6-1
	CNTNAP2	ENST00000636870.1	TSL:5	n.1639+10A>G		intron	N/A
	CNTNAP2	ENST00000637694.1	TSL:5	n.1680+10A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31662 AN: 151926 Hom.: 3589 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.230 AC: 57702 AN: 251242 AF XY: 0.228

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.371

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.190 AC: 275766 AN: 1453812 Hom.: 28643 Cov.: 28 AF XY: 0.193 AC XY: 139589 AN XY: 723752

African (AFR) AF: 0.232 AC: 7731 AN: 33318

American (AMR) AF: 0.340 AC: 15203 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 3543 AN: 26076

East Asian (EAS) AF: 0.329 AC: 13042 AN: 39650

South Asian (SAS) AF: 0.309 AC: 26563 AN: 86070

European-Finnish (FIN) AF: 0.182 AC: 9723 AN: 53398

Middle Eastern (MID) AF: 0.155 AC: 890 AN: 5750

European-Non Finnish (NFE) AF: 0.170 AC: 187537 AN: 1104758

Other (OTH) AF: 0.192 AC: 11534 AN: 60094

GnomAD4 genome AF: 0.209 AC: 31706 AN: 152044 Hom.: 3603 Cov.: 32 AF XY: 0.212 AC XY: 15790 AN XY: 74320

African (AFR) AF: 0.230 AC: 9540 AN: 41468

American (AMR) AF: 0.283 AC: 4331 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 462 AN: 3470

East Asian (EAS) AF: 0.363 AC: 1874 AN: 5158

South Asian (SAS) AF: 0.320 AC: 1544 AN: 4820

European-Finnish (FIN) AF: 0.183 AC: 1933 AN: 10562

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11391 AN: 67972

Other (OTH) AF: 0.184 AC: 387 AN: 2104

Alfa AF: 0.182 Hom.: 941

Bravo AF: 0.216

Asia WGS AF: 0.294 AC: 1020 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Cortical dysplasia-focal epilepsy syndrome (4)
-	-	2	not provided (2)
-	-	1	Pitt-Hopkins-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.79
PhyloP100		0.87
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: rs2286127; hg19: chr7-147183143; COSMIC: COSV62158213;