16-76521280-A-T

Position:

• chr16-76521280-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000611870.5(CNTNAP4):​c.2506A>T​(p.Ile836Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00958 in 1,611,866 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0072 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (105 hom.)
• Consequence: CNTNAP4 ENST00000611870.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.86

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007897258).
• BP6: Variant 16-76521280-A-T is Benign according to our data. Variant chr16-76521280-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3056004.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0072 (1095/152004) while in subpopulation SAS AF= 0.0222 (107/4816). AF 95% confidence interval is 0.0188. There are 7 homozygotes in gnomad4. There are 503 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP4	NM_033401.5	c.2506A>T	p.Ile836Phe	missense_variant	16/24	ENST00000611870.5	NP_207837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP4	ENST00000611870.5	c.2506A>T	p.Ile836Phe	missense_variant	16/24	1	NM_033401.5	ENSP00000479811	P4

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1095 AN: 151886 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00545

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.00171

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00843 AC: 2083 AN: 247124 Hom.: 20 AF XY: 0.00902 AC XY: 1210 AN XY: 134132

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00430

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.00223

Gnomad NFE exome AF: 0.00915

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00982 AC: 14340 AN: 1459862 Hom.: 105 Cov.: 32 AF XY: 0.0101 AC XY: 7345 AN XY: 726188

Gnomad4 AFR exome AF: 0.00159

Gnomad4 AMR exome AF: 0.00470

Gnomad4 ASJ exome AF: 0.0230

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0179

Gnomad4 FIN exome AF: 0.00229

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00951

GnomAD4 genome AF: 0.00720 AC: 1095 AN: 152004 Hom.: 7 Cov.: 32 AF XY: 0.00677 AC XY: 503 AN XY: 74298

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00544

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.00171

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00844 Hom.: 5

Bravo AF: 0.00701

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00248 AC: 9

ESP6500EA AF: 0.0112 AC: 91

ExAC AF: 0.00830 AC: 1002

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CNTNAP4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;T;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
MetaRNN	Benign	0.0079	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	.;.;.;.;D;D
REVEL	Benign	0.18
Sift	Benign	0.26	.;.;.;.;T;T
Sift4G	Uncertain	0.045	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;D
Vest4		0.71
MVP		0.51
MPC		0.20
ClinPred		0.053	T
GERP RS		5.0
Varity_R		0.20
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs112577515; hg19: chr16-76555177;