rs1547597

Variant names:

• chr7-148269658-G-A
• rs1547597
• NM_014141.6:c.3475+2532G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_014141.6(CNTNAP2):​c.3475+2532G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.759 in 152,188 control chromosomes in the GnomAD database, including 43,979 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (43979 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.156
• 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

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.3475+2532G>A		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.3475+2532G>A		intron	N/A	ENSP00000354778.3	Q9UHC6-1
	CNTNAP2	ENST00000628930.2	TSL:2	c.652+2532G>A		intron	N/A	ENSP00000487516.1	B7Z1Y6
	CNTNAP2	ENST00000627772.2	TSL:2	n.1648+2532G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115434 AN: 152070 Hom.: 43956 Cov.: 32

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.780

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.725

Gnomad OTH AF: 0.775

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.759 AC: 115502 AN: 152188 Hom.: 43979 Cov.: 32 AF XY: 0.767 AC XY: 57035 AN XY: 74394

African (AFR) AF: 0.756 AC: 31390 AN: 41510

American (AMR) AF: 0.781 AC: 11942 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3048 AN: 3472

East Asian (EAS) AF: 0.772 AC: 3987 AN: 5166

South Asian (SAS) AF: 0.872 AC: 4207 AN: 4826

European-Finnish (FIN) AF: 0.863 AC: 9156 AN: 10610

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.725 AC: 49270 AN: 67990

Other (OTH) AF: 0.773 AC: 1632 AN: 2112

Alfa AF: 0.759 Hom.: 7631

Bravo AF: 0.752

Asia WGS AF: 0.830 AC: 2884 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	15
DANN	Benign	0.37
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1547597; hg19: chr7-147966750;