chr7-147108140-G-T

Position:

• chr7-147108140-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_014141.6(CNTNAP2):​c.551-7G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNTNAP2 NM_014141.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000006417
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -1.19

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-147108140-G-T is Benign according to our data. Variant chr7-147108140-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 468436.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-147108140-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.551-7G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.551-7G>T		splice_region_variant, 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.551-7G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014141.6	ENSP00000354778	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 13 AN: 150186 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00100

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.000485

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000191 AC: 276 AN: 1447354 Hom.: 0 Cov.: 32 AF XY: 0.000193 AC XY: 139 AN XY: 719872

Gnomad4 AFR exome AF: 0.000675

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.000779

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.000513

Gnomad4 FIN exome AF: 0.000135

Gnomad4 NFE exome AF: 0.0000868

Gnomad4 OTH exome AF: 0.000369

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000866 AC: 13 AN: 150186 Hom.: 0 Cov.: 32 AF XY: 0.000123 AC XY: 9 AN XY: 73200

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00100

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.000485

Alfa AF: 0.00845 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cortical dysplasia-focal epilepsy syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.11
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000064
dbscSNV1_RF	Benign	0.010
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: rs768621629; hg19: chr7-146805232;