rs587780319

Positions:

• chr7-147562206-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000361727.8(CNTNAP2):​c.1846C>T​(p.Pro616Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P616L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNTNAP2 ENST00000361727.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.04

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29063833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1846C>T	p.Pro616Ser	missense_variant	12/24	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1846C>T	p.Pro616Ser	missense_variant	12/14		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1846C>T	p.Pro616Ser	missense_variant	12/24	1	NM_014141.6	ENSP00000354778	P1
CNTNAP2	ENST00000636870.1	n.1708C>T		non_coding_transcript_exon_variant	10/22	5
CNTNAP2	ENST00000637825.1	n.1329C>T		non_coding_transcript_exon_variant	9/14	5
CNTNAP2	ENST00000638117.1	n.1749C>T		non_coding_transcript_exon_variant	11/13	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 30, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 31, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.13
Sift	Benign	0.88	T;.
Sift4G	Benign	0.75	T;.
Polyphen		0.58	P;P
Vest4		0.71
MutPred		0.41		Gain of disorder (P = 0.1266);Gain of disorder (P = 0.1266);
MVP		0.65
MPC		0.14
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.11
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs587780319; hg19: chr7-147259298; COSMIC: COSV62189267;