rs34251012

Positions:

• chr16-76448850-C-G

Variant summary

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

The NM_033401.5(CNTNAP4):​c.826C>G​(p.Leu276Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,613,098 control chromosomes in the GnomAD database, including 634 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 0.031 (98 hom., cov: 31)
  • Exomes 𝑓: 0.022 (536 hom.)
• Consequence: CNTNAP4 NM_033401.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04

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=0.0036981702).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP4	NM_033401.5	c.826C>G	p.Leu276Val	missense_variant	6/24	ENST00000611870.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP4	ENST00000611870.5	c.826C>G	p.Leu276Val	missense_variant	6/24	1	NM_033401.5	P4

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4686 AN: 152060 Hom.: 98 Cov.: 31

Gnomad AFR AF: 0.0580

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.00737

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0247 AC: 6163 AN: 249732 Hom.: 155 AF XY: 0.0250 AC XY: 3370 AN XY: 134914

Gnomad AFR exome AF: 0.0603

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0397

Gnomad EAS exome AF: 0.00290

Gnomad SAS exome AF: 0.0608

Gnomad FIN exome AF: 0.00856

Gnomad NFE exome AF: 0.0183

Gnomad OTH exome AF: 0.0234

GnomAD4 exome AF: 0.0216 AC: 31530 AN: 1460920 Hom.: 536 Cov.: 32 AF XY: 0.0226 AC XY: 16416 AN XY: 726654

Gnomad4 AFR exome AF: 0.0613

Gnomad4 AMR exome AF: 0.0153

Gnomad4 ASJ exome AF: 0.0376

Gnomad4 EAS exome AF: 0.00141

Gnomad4 SAS exome AF: 0.0580

Gnomad4 FIN exome AF: 0.00935

Gnomad4 NFE exome AF: 0.0184

Gnomad4 OTH exome AF: 0.0271

GnomAD4 genome AF: 0.0308 AC: 4688 AN: 152178 Hom.: 98 Cov.: 31 AF XY: 0.0301 AC XY: 2242 AN XY: 74386

Gnomad4 AFR AF: 0.0580

Gnomad4 AMR AF: 0.0226

Gnomad4 ASJ AF: 0.0432

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.0529

Gnomad4 FIN AF: 0.00737

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0214 Hom.: 31

Bravo AF: 0.0326

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0215 AC: 83

ESP6500AA AF: 0.0607 AC: 267

ESP6500EA AF: 0.0187 AC: 161

ExAC AF: 0.0261 AC: 3167

Asia WGS AF: 0.0440 AC: 154 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T;T;T;.;.;.
Eigen	Benign	-0.011
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T;T;T;T;T;T
MetaRNN	Benign	0.0037	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	.;.;.;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.41	.;.;.;.;T;T
Sift4G	Benign	0.50	T;T;T;T;T;T
Polyphen		0.40	B;.;.;.;.;B
Vest4		0.30
MPC		0.026
ClinPred		0.0088	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.17

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: rs34251012; hg19: chr16-76482747; COSMIC: COSV56678060;