16-76498686-A-G

Variant names:

• chr16-76498686-A-G
• rs12933808
• NM_033401.5:c.2357A>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.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. 12/20 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 0.84 (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
• 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=6.0220145E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 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.2357A>G	p.Gln786Arg	missense	Exon 15 of 24	NP_207837.2	Q9C0A0-1
	CNTNAP4	NM_001322181.2		c.2354A>G	p.Gln785Arg	missense	Exon 15 of 24	NP_001309110.1
	CNTNAP4	NM_001322188.2		c.2357A>G	p.Gln786Arg	missense	Exon 15 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.2357A>G	p.Gln786Arg	missense	Exon 15 of 24	ENSP00000479811.1	Q9C0A0-1
	CNTNAP4	ENST00000622250.4	TSL:1	c.2213A>G	p.Gln738Arg	missense	Exon 14 of 23	ENSP00000477698.1	A0A087WTA1
	ENSG00000287694	ENST00000655556.1		n.2357A>G		non_coding_transcript_exon	Exon 15 of 25	ENSP00000499374.1	A0A590UJB1

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

GnomAD2 exomes AF: 0.888 AC: 217221 AN: 244624 AF XY: 0.891

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 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

African (AFR) AF: 0.665 AC: 22092 AN: 33230

American (AMR) AF: 0.905 AC: 39636 AN: 43820

Ashkenazi Jewish (ASJ) AF: 0.946 AC: 24596 AN: 25996

East Asian (EAS) AF: 0.977 AC: 38686 AN: 39592

South Asian (SAS) AF: 0.876 AC: 73897 AN: 84354

European-Finnish (FIN) AF: 0.841 AC: 44822 AN: 53290

Middle Eastern (MID) AF: 0.910 AC: 5242 AN: 5758

European-Non Finnish (NFE) AF: 0.910 AC: 1009560 AN: 1109036

Other (OTH) AF: 0.901 AC: 54139 AN: 60114

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

African (AFR) AF: 0.670 AC: 27764 AN: 41446

American (AMR) AF: 0.895 AC: 13678 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.946 AC: 3284 AN: 3472

East Asian (EAS) AF: 0.973 AC: 5022 AN: 5160

South Asian (SAS) AF: 0.887 AC: 4281 AN: 4826

European-Finnish (FIN) AF: 0.836 AC: 8851 AN: 10586

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.907 AC: 61728 AN: 68020

Other (OTH) AF: 0.859 AC: 1814 AN: 2112

Alfa AF: 0.892 Hom.: 210626

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 v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	6.0e-7	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.037
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.50
Sift	Benign	0.70	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.15
MPC		0.022
ClinPred		0.00066	T
GERP RS		-0.49
Varity_R		0.025
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12933808; hg19: chr16-76532583; COSMIC: COSV107323187; COSMIC: COSV107323187;