chr16-76553305-T-G

Variant names:

• chr16-76553305-T-G
• rs7202925
• NM_033401.5:c.3465T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033401.5(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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (6851 hom., cov: 33)
  • Exomes 𝑓: 0.30 (65260 hom.)
• Consequence: CNTNAP4 NM_033401.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0640
• Publications: 25 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: Benign. The variant received -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.

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.3465T>G	p.Asp1155Glu	missense	Exon 22 of 24	NP_207837.2	Q9C0A0-1
	CNTNAP4	NM_001322181.2		c.3462T>G	p.Asp1154Glu	missense	Exon 22 of 24	NP_001309110.1
	CNTNAP4	NM_001322188.2		c.3465T>G	p.Asp1155Glu	missense	Exon 22 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.3465T>G	p.Asp1155Glu	missense	Exon 22 of 24	ENSP00000479811.1	Q9C0A0-1
	CNTNAP4	ENST00000622250.4	TSL:1	c.3321T>G	p.Asp1107Glu	missense	Exon 21 of 23	ENSP00000477698.1	A0A087WTA1
	ENSG00000287694	ENST00000655556.1		n.3465T>G		non_coding_transcript_exon	Exon 22 of 25	ENSP00000499374.1	A0A590UJB1

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

GnomAD2 exomes AF: 0.286 AC: 70410 AN: 245814 AF XY: 0.289

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 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

African (AFR) AF: 0.343 AC: 11394 AN: 33260

American (AMR) AF: 0.215 AC: 9564 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6402 AN: 26048

East Asian (EAS) AF: 0.291 AC: 11498 AN: 39478

South Asian (SAS) AF: 0.359 AC: 30817 AN: 85826

European-Finnish (FIN) AF: 0.262 AC: 13950 AN: 53300

Middle Eastern (MID) AF: 0.179 AC: 1027 AN: 5736

European-Non Finnish (NFE) AF: 0.298 AC: 328915 AN: 1104260

Other (OTH) AF: 0.290 AC: 17386 AN: 59958

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

African (AFR) AF: 0.347 AC: 14425 AN: 41514

American (AMR) AF: 0.234 AC: 3575 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 795 AN: 3472

East Asian (EAS) AF: 0.279 AC: 1443 AN: 5164

South Asian (SAS) AF: 0.353 AC: 1704 AN: 4826

European-Finnish (FIN) AF: 0.260 AC: 2756 AN: 10580

Middle Eastern (MID) AF: 0.185 AC: 54 AN: 292

European-Non Finnish (NFE) AF: 0.293 AC: 19885 AN: 67966

Other (OTH) AF: 0.255 AC: 539 AN: 2116

Alfa AF: 0.287 Hom.: 31778

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 v4.9

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
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.064	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.064
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.036
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7202925; hg19: chr16-76587202; COSMIC: COSV56665398; COSMIC: COSV56665398;