chr7-147108136-T-G

Variant names:

• chr7-147108136-T-G
• rs78223661
• NM_014141.6:c.551-11T>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_014141.6(CNTNAP2):​c.551-11T>G variant causes a 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 intron
• Scores: Splicing: ADA: 0.0001910
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.0860
• Publications: 2 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 -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 VariationId is 95575.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.551-11T>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.551-11T>G		intron	N/A	ENSP00000354778.3	Q9UHC6-1
	CNTNAP2	ENST00000636561.1	TSL:5	n.454-11T>G		intron	N/A
	CNTNAP2	ENST00000636870.1	TSL:5	n.413-11T>G		intron	N/A

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

GnomAD2 exomes AF: 0.000626 AC: 156 AN: 249056 AF XY: 0.000541

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 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

African (AFR) AF: 0.00683 AC: 228 AN: 33360

American (AMR) AF: 0.000651 AC: 29 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26084

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39626

South Asian (SAS) AF: 0.0000814 AC: 7 AN: 86014

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52756

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5704

European-Non Finnish (NFE) AF: 0.000219 AC: 243 AN: 1109148

Other (OTH) AF: 0.000780 AC: 47 AN: 60222

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

African (AFR) AF: 0.00649 AC: 269 AN: 41454

American (AMR) AF: 0.000984 AC: 15 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5162

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67934

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.267 Hom.: 2815

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	-	1	Cortical dysplasia-focal epilepsy syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.4
DANN	Benign	0.51
PhyloP100		0.086
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs78223661; hg19: chr7-146805228;