chr3-2736310-G-C

Position:

• chr3-2736310-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_175607.3(CNTN4):​c.151G>C​(p.Glu51Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CNTN4 NM_175607.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.72

Genes affected

CNTN4 (HGNC:2174): (contactin 4) This gene encodes a member of the contactin family of immunoglobulins. Contactins are axon-associated cell adhesion molecules that function in neuronal network formation and plasticity. The encoded protein is a glycosylphosphatidylinositol-anchored neuronal membrane protein that may play a role in the formation of axon connections in the developing nervous system. Deletion or mutation of this gene may play a role in 3p deletion syndrome and autism spectrum disorders. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2011]

CNTN4 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.42383382).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN4	NM_175607.3	c.151G>C	p.Glu51Gln	missense_variant	5/25	ENST00000418658.6	NP_783200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN4	ENST00000418658.6	c.151G>C	p.Glu51Gln	missense_variant	5/25	5	NM_175607.3	ENSP00000396010.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461532 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2022

The c.151G>C (p.E51Q) alteration is located in exon 4 (coding exon 2) of the CNTN4 gene. This alteration results from a G to C substitution at nucleotide position 151, causing the glutamic acid (E) at amino acid position 51 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	.;.;T;T;.;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T;T;.;.;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.42	T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.31	.;.;N;N;.;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.72	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.067	T;T;T;T;T;T
Sift4G	Benign	0.27	T;D;T;T;T;T
Polyphen		0.98	.;.;D;D;.;D
Vest4		0.33, 0.29, 0.29
MutPred		0.40		Gain of MoRF binding (P = 0.0389);Gain of MoRF binding (P = 0.0389);Gain of MoRF binding (P = 0.0389);Gain of MoRF binding (P = 0.0389);.;Gain of MoRF binding (P = 0.0389);
MVP		0.54
MPC		0.18
ClinPred		0.85	D
GERP RS		5.2
Varity_R		0.16
gMVP		0.52

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: rs968013770; hg19: chr3-2777994;