16-76553305-T-G

Position:

• chr16-76553305-T-G

Variant summary

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

The ENST00000611870.5(CNTNAP4):​c.3465T>G​(p.Asp1155Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,604,446 control chromosomes in the GnomAD database, including 72,111 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.30 (6851 hom., cov: 33)
  • Exomes 𝑓: 0.30 (65260 hom.)
• Consequence: CNTNAP4 ENST00000611870.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0640

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055819154).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP4	NM_033401.5	c.3465T>G	p.Asp1155Glu	missense_variant	22/24	ENST00000611870.5	NP_207837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP4	ENST00000611870.5	c.3465T>G	p.Asp1155Glu	missense_variant	22/24	1	NM_033401.5	ENSP00000479811	P4

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45326 AN: 152018 Hom.: 6833 Cov.: 33

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.247

GnomAD3 exomes AF: 0.286 AC: 70410 AN: 245814 Hom.: 10458 AF XY: 0.289 AC XY: 38567 AN XY: 133412

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.285

Gnomad SAS exome AF: 0.363

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.297 AC: 430953 AN: 1452310 Hom.: 65260 Cov.: 31 AF XY: 0.298 AC XY: 214782 AN XY: 721484

Gnomad4 AFR exome AF: 0.343

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.291

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.262

Gnomad4 NFE exome AF: 0.298

Gnomad4 OTH exome AF: 0.290

GnomAD4 genome AF: 0.298 AC: 45376 AN: 152136 Hom.: 6851 Cov.: 33 AF XY: 0.296 AC XY: 22032 AN XY: 74370

Gnomad4 AFR AF: 0.347

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.255

Alfa AF: 0.280 Hom.: 15853

Bravo AF: 0.294

TwinsUK AF: 0.301 AC: 1116

ALSPAC AF: 0.294 AC: 1133

ESP6500AA AF: 0.334 AC: 1309

ESP6500EA AF: 0.279 AC: 2328

ExAC AF: 0.292 AC: 35340

Asia WGS AF: 0.370 AC: 1287 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.2
DANN	Benign	0.62
DEOGEN2	Benign	0.062	T;T;T;.;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.064	T;T;T;T;T;T
MetaRNN	Benign	0.0056	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.0	.;.;.;.;N;N
REVEL	Benign	0.036
Sift	Benign	1.0	.;.;.;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;B
Vest4		0.047
MutPred		0.30		.;.;.;.;.;Gain of disorder (P = 0.1807);
MPC		0.021
ClinPred		0.00062	T
GERP RS		3.3
Varity_R		0.043
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7202925; hg19: chr16-76587202; COSMIC: COSV56665398; COSMIC: COSV56665398;