rs73471053

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014141.6(CNTNAP2):​c.1119G>A​(p.Thr373=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,613,554 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 17 hom., cov: 32)
Exomes 𝑓: 0.00095 ( 23 hom. )

Consequence

CNTNAP2
NM_014141.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.38
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 7-147132280-G-A is Benign according to our data. Variant chr7-147132280-G-A is described in ClinVar as [Benign]. Clinvar id is 128799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-147132280-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.38 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00894 (1359/152056) while in subpopulation AFR AF= 0.0316 (1309/41462). AF 95% confidence interval is 0.0301. There are 17 homozygotes in gnomad4. There are 632 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CNTNAP2NM_014141.6 linkuse as main transcriptc.1119G>A p.Thr373= synonymous_variant 8/24 ENST00000361727.8 NP_054860.1
CNTNAP2XM_017011950.3 linkuse as main transcriptc.1119G>A p.Thr373= synonymous_variant 8/14 XP_016867439.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CNTNAP2ENST00000361727.8 linkuse as main transcriptc.1119G>A p.Thr373= synonymous_variant 8/241 NM_014141.6 ENSP00000354778 P1Q9UHC6-1

Frequencies

GnomAD3 genomes
AF:
0.00894
AC:
1358
AN:
151938
Hom.:
17
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0316
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00230
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00481
GnomAD3 exomes
AF:
0.00229
AC:
575
AN:
251280
Hom.:
9
AF XY:
0.00151
AC XY:
205
AN XY:
135808
show subpopulations
Gnomad AFR exome
AF:
0.0308
Gnomad AMR exome
AF:
0.00162
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00130
GnomAD4 exome
AF:
0.000949
AC:
1387
AN:
1461498
Hom.:
23
Cov.:
32
AF XY:
0.000855
AC XY:
622
AN XY:
727062
show subpopulations
Gnomad4 AFR exome
AF:
0.0338
Gnomad4 AMR exome
AF:
0.00159
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000197
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000225
Gnomad4 OTH exome
AF:
0.00220
GnomAD4 genome
AF:
0.00894
AC:
1359
AN:
152056
Hom.:
17
Cov.:
32
AF XY:
0.00850
AC XY:
632
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.0316
Gnomad4 AMR
AF:
0.00230
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00476
Alfa
AF:
0.00439
Hom.:
3
Bravo
AF:
0.0103
Asia WGS
AF:
0.00260
AC:
10
AN:
3476
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxApr 04, 2013This 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. -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 03, 2017- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Cortical dysplasia-focal epilepsy syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 09, 2016This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
CADD
Benign
0.10
DANN
Benign
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs73471053; hg19: chr7-146829372; API