rs78223661

Positions:

• chr7-147108136-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_014141.6(CNTNAP2):​c.551-11T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000543 in 1,609,390 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: CNTNAP2 NM_014141.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001910
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0860

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-147108136-T-G is Benign according to our data. Variant chr7-147108136-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95575.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chr7-147108136-T-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.551-11T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.551-11T>G		splice_polypyrimidine_tract_variant, intron_variant			XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.551-11T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014141.6	ENSP00000354778	P1

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 302 AN: 151828 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000985

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000626 AC: 156 AN: 249056 Hom.: 2 AF XY: 0.000541 AC XY: 73 AN XY: 134830

Gnomad AFR exome AF: 0.00687

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000950

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000392 AC: 571 AN: 1457444 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 263 AN XY: 725248

Gnomad4 AFR exome AF: 0.00683

Gnomad4 AMR exome AF: 0.000651

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000814

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.000780

GnomAD4 genome AF: 0.00199 AC: 303 AN: 151946 Hom.: 2 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74266

Gnomad4 AFR AF: 0.00649

Gnomad4 AMR AF: 0.000984

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.162 Hom.: 962

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 20, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 12, 2013	- -

Cortical dysplasia-focal epilepsy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.4
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.12
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: rs78223661; hg19: chr7-146805228;