7-148172578-T-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.3010+100T>C		intron_variant	Intron 18 of 23	ENST00000361727.8	NP_054860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.3010+100T>C		intron_variant	Intron 18 of 23	1	NM_014141.6	ENSP00000354778.3

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

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.411

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.506

Gnomad4 SAS exome AF: 0.369

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.224

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

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.204

Gnomad4 EAS AF: 0.519

Gnomad4 SAS AF: 0.395

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.242

Alfa AF: 0.200 Hom.: 1649

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.3
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs2074711; hg19: chr7-147869670;