NM_014141.6:c.3010+100T>C

Variant names:

• chr7-148172578-T-C
• rs2074711
• NM_014141.6:c.3010+100T>C

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.3010+100T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,079,348 control chromosomes in the GnomAD database, including 31,264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4373 hom., cov: 33)
  • Exomes 𝑓: 0.22 (26891 hom.)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.142
• 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: 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=-0.66).
• BP6: Variant 7-148172578-T-C is Benign according to our data. Variant chr7-148172578-T-C is described in ClinVar as Benign. ClinVar VariationId is 675151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.503 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.3010+100T>C		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.3010+100T>C		intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000628930.2	TSL:2	c.187+100T>C		intron	N/A	ENSP00000487516.1
	CNTNAP2	ENST00000627772.2	TSL:2	n.1183+100T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33865 AN: 151952 Hom.: 4350 Cov.: 33

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.216 AC: 200709 AN: 927278 Hom.: 26891 AF XY: 0.221 AC XY: 106691 AN XY: 483388

African (AFR) AF: 0.200 AC: 4654 AN: 23292

American (AMR) AF: 0.411 AC: 17992 AN: 43746

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 4728 AN: 22828

East Asian (EAS) AF: 0.506 AC: 18821 AN: 37194

South Asian (SAS) AF: 0.369 AC: 27485 AN: 74562

European-Finnish (FIN) AF: 0.236 AC: 10505 AN: 44530

Middle Eastern (MID) AF: 0.192 AC: 925 AN: 4830

European-Non Finnish (NFE) AF: 0.167 AC: 105953 AN: 633196

Other (OTH) AF: 0.224 AC: 9646 AN: 43100

GnomAD4 genome AF: 0.223 AC: 33929 AN: 152070 Hom.: 4373 Cov.: 33 AF XY: 0.235 AC XY: 17476 AN XY: 74346

African (AFR) AF: 0.202 AC: 8397 AN: 41472

American (AMR) AF: 0.327 AC: 4991 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 709 AN: 3470

East Asian (EAS) AF: 0.519 AC: 2675 AN: 5154

South Asian (SAS) AF: 0.395 AC: 1904 AN: 4820

European-Finnish (FIN) AF: 0.243 AC: 2576 AN: 10582

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11924 AN: 67990

Other (OTH) AF: 0.242 AC: 510 AN: 2108

Alfa AF: 0.199 Hom.: 1814

Bravo AF: 0.227

Asia WGS AF: 0.468 AC: 1626 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.3
DANN	Benign	0.79
PhyloP100		-0.14
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: rs2074711; hg19: chr7-147869670;