chr16-76489748-C-T

Variant names:

• chr16-76489748-C-T
• rs777746016
• NM_033401.5:c.1945C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033401.5(CNTNAP4):​c.1945C>T​(p.Pro649Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CNTNAP4 NM_033401.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06812379).

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.1945C>T	p.Pro649Ser	missense	Exon 13 of 24	NP_207837.2	Q9C0A0-1
	CNTNAP4	NM_001322181.2		c.1942C>T	p.Pro648Ser	missense	Exon 13 of 24	NP_001309110.1
	CNTNAP4	NM_001322188.2		c.1945C>T	p.Pro649Ser	missense	Exon 13 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.1945C>T	p.Pro649Ser	missense	Exon 13 of 24	ENSP00000479811.1	Q9C0A0-1
	CNTNAP4	ENST00000622250.4	TSL:1	c.1801C>T	p.Pro601Ser	missense	Exon 12 of 23	ENSP00000477698.1	A0A087WTA1
	ENSG00000287694	ENST00000655556.1		n.1945C>T		non_coding_transcript_exon	Exon 13 of 25	ENSP00000499374.1	A0A590UJB1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000850 AC: 2 AN: 235220 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000949

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1452116 Hom.: 0 Cov.: 30 AF XY: 0.00000416 AC XY: 3 AN XY: 721310

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 43592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106970

Other (OTH) AF: 0.00 AC: 0 AN: 60042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00103286), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.41
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.085
Sift	Benign	0.69	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.45		Gain of disorder (P = 0.0993)
MVP		0.45
MPC		0.021
ClinPred		0.022	T
GERP RS		2.5
Varity_R		0.033
gMVP		0.29
Mutation Taster		=94/6	polymorphism

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: rs777746016; hg19: chr16-76523645; COSMIC: COSV56675561;