chr16-76498686-A-G

Variant names:

• chr16-76498686-A-G
• rs12933808
• NM_033401.5:c.2357A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033401.5(CNTNAP4):​c.2357A>G​(p.Gln786Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.896 in 1,607,296 control chromosomes in the GnomAD database, including 647,855 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.84 (54342 hom., cov: 32)
  • Exomes 𝑓: 0.90 (593513 hom.)
• Consequence: CNTNAP4 NM_033401.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0370

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.0220145E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP4	NM_033401.5	c.2357A>G	p.Gln786Arg	missense_variant	Exon 15 of 24	ENST00000611870.5	NP_207837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP4	ENST00000611870.5	c.2357A>G	p.Gln786Arg	missense_variant	Exon 15 of 24	1	NM_033401.5	ENSP00000479811.1
ENSG00000287694	ENST00000655556.1	n.2357A>G		non_coding_transcript_exon_variant	Exon 15 of 25			ENSP00000499374.1

Frequencies

GnomAD3 genomes AF: 0.838 AC: 127422 AN: 151986 Hom.: 54308 Cov.: 32

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.895

Gnomad ASJ AF: 0.946

Gnomad EAS AF: 0.974

Gnomad SAS AF: 0.887

Gnomad FIN AF: 0.836

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.862

GnomAD3 exomes AF: 0.888 AC: 217221 AN: 244624 Hom.: 96972 AF XY: 0.891 AC XY: 118177 AN XY: 132672

Gnomad AFR exome AF: 0.664

Gnomad AMR exome AF: 0.906

Gnomad ASJ exome AF: 0.945

Gnomad EAS exome AF: 0.975

Gnomad SAS exome AF: 0.875

Gnomad FIN exome AF: 0.842

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.898

GnomAD4 exome AF: 0.902 AC: 1312670 AN: 1455190 Hom.: 593513 Cov.: 39 AF XY: 0.902 AC XY: 652620 AN XY: 723540

Gnomad4 AFR exome AF: 0.665

Gnomad4 AMR exome AF: 0.905

Gnomad4 ASJ exome AF: 0.946

Gnomad4 EAS exome AF: 0.977

Gnomad4 SAS exome AF: 0.876

Gnomad4 FIN exome AF: 0.841

Gnomad4 NFE exome AF: 0.910

Gnomad4 OTH exome AF: 0.901

GnomAD4 genome AF: 0.838 AC: 127505 AN: 152106 Hom.: 54342 Cov.: 32 AF XY: 0.838 AC XY: 62312 AN XY: 74370

Gnomad4 AFR AF: 0.670

Gnomad4 AMR AF: 0.895

Gnomad4 ASJ AF: 0.946

Gnomad4 EAS AF: 0.973

Gnomad4 SAS AF: 0.887

Gnomad4 FIN AF: 0.836

Gnomad4 NFE AF: 0.907

Gnomad4 OTH AF: 0.859

Alfa AF: 0.899 Hom.: 103717

Bravo AF: 0.837

TwinsUK AF: 0.906 AC: 3358

ALSPAC AF: 0.906 AC: 3492

ESP6500AA AF: 0.697 AC: 2847

ESP6500EA AF: 0.910 AC: 7723

ExAC AF: 0.880 AC: 106479

Asia WGS AF: 0.883 AC: 3074 AN: 3478

EpiCase AF: 0.919

EpiControl AF: 0.915

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	3.1
DANN	Benign	0.92
DEOGEN2	Benign	0.0058	T;T;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.35	T;T;T;T;T;T
MetaRNN	Benign	6.0e-7	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.43	.;.;.;.;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.70	.;.;.;.;T;T
Sift4G	Benign	0.44	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;B
Vest4		0.15
MPC		0.022
ClinPred		0.00066	T
GERP RS		-0.49
Varity_R		0.025
gMVP		0.15

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: rs12933808; hg19: chr16-76532583;