16-76479469-G-C

Position:

• chr16-76479469-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000611870.5(CNTNAP4):​c.1813G>C​(p.Gly605Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CNTNAP4 ENST00000611870.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.92

Genes affected

CNTNAP4 (HGNC:18747): (contactin associated protein family member 4) This gene encodes a member of the neurexin protein family. Members of this family function in the vertebrate nervous system as cell adhesion molecules and receptors. This protein 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, and thrombospondin N-terminal-like domains. This protein may also play a role in proper neurotransmission in the dopaminergic and GABAergic systems and mutations in this gene may be associated with certain psychiatric illnesses. A polymorphism in an intron of this gene may be associated with longevity. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP4	NM_033401.5	c.1813G>C	p.Gly605Arg	missense_variant	12/24	ENST00000611870.5	NP_207837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP4	ENST00000611870.5	c.1813G>C	p.Gly605Arg	missense_variant	12/24	1	NM_033401.5	ENSP00000479811	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2024

The c.1813G>C (p.G605R) alteration is located in exon 12 (coding exon 12) of the CNTNAP4 gene. This alteration results from a G to C substitution at nucleotide position 1813, causing the glycine (G) at amino acid position 605 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;T;T;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.7	.;.;.;.;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	.;.;.;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.97	D;.;.;.;.;D
Vest4		0.90
MutPred		0.67		.;.;.;.;.;Loss of glycosylation at S607 (P = 0.044);
MVP		0.73
MPC		0.15
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.31
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-76513366;