16-76452686-G-A

Variant names:

• chr16-76452686-G-A
• NM_033401.5:c.1250G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033401.5(CNTNAP4):​c.1250G>A​(p.Gly417Glu) variant causes a missense change. 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 (★). Synonymous variant affecting the same amino acid position (i.e. G417G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNTNAP4 NM_033401.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95
• Publications: 0 publications found

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]

ENSG00000287694 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033401.5. 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
	CNTNAP4	NM_033401.5	MANE Select	c.1250G>A	p.Gly417Glu	missense	Exon 8 of 24	NP_207837.2	Q9C0A0-1
	CNTNAP4	NM_001322181.2		c.1247G>A	p.Gly416Glu	missense	Exon 8 of 24	NP_001309110.1
	CNTNAP4	NM_001322188.2		c.1250G>A	p.Gly417Glu	missense	Exon 8 of 25	NP_001309117.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP4	ENST00000611870.5	TSL:1 MANE Select	c.1250G>A	p.Gly417Glu	missense	Exon 8 of 24	ENSP00000479811.1	Q9C0A0-1
	CNTNAP4	ENST00000622250.4	TSL:1	c.1106G>A	p.Gly369Glu	missense	Exon 7 of 23	ENSP00000477698.1	A0A087WTA1
	ENSG00000287694	ENST00000655556.1		n.1250G>A		non_coding_transcript_exon	Exon 8 of 25	ENSP00000499374.1	A0A590UJB1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.14	T
PhyloP100		4.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.51
Sift	Benign	0.51	T
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.64		Loss of catalytic residue at S419 (P = 0.0999)
MVP		0.88
MPC		0.049
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.34
gMVP		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

Other links and lift over

hg19: chr16-76486583;