3-2571548-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_175607.3(CNTN4):c.45G>C(p.Leu15Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00235 in 1,613,036 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (37 hom.)
• Consequence: CNTN4 NM_175607.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.03

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057327747).
• BP6: Variant 3-2571548-G-C is Benign according to our data. Variant chr3-2571548-G-C is described in ClinVar as [Benign]. Clinvar id is 783213.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1814/152318) while in subpopulation AFR AF= 0.0415 (1723/41562). AF 95% confidence interval is 0.0398. There are 39 homozygotes in gnomad4. There are 866 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1787 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN4	NM_175607.3	c.45G>C	p.Leu15Phe	missense_variant	4/25	ENST00000418658.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN4	ENST00000418658.6	c.45G>C	p.Leu15Phe	missense_variant	4/25	5	NM_175607.3	P1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1787 AN: 152200 Hom.: 36 Cov.: 33

Gnomad AFR AF: 0.0410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00312 AC: 777 AN: 249326 Hom.: 12 AF XY: 0.00234 AC XY: 316 AN XY: 135260

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00135 AC: 1972 AN: 1460718 Hom.: 37 Cov.: 30 AF XY: 0.00121 AC XY: 879 AN XY: 726768

Gnomad4 AFR exome AF: 0.0427

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.0119 AC: 1814 AN: 152318 Hom.: 39 Cov.: 33 AF XY: 0.0116 AC XY: 866 AN XY: 74482

Gnomad4 AFR AF: 0.0415

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00157 Hom.: 2

Bravo AF: 0.0136

ESP6500AA AF: 0.0419 AC: 158

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.00384 AC: 464

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	21
Dann	Benign	0.91
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.21	T;T;.;.;T;T
MetaRNN	Benign	0.0057	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.34	N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.63	T;T;T;T;T;T
Sift4G	Benign	0.76	T;T;T;T;T;T
Polyphen		0.0	.;.;B;B;.;B
Vest4		0.38, 0.35, 0.35
MutPred		0.51		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.47
MPC		0.12
ClinPred		0.022	T
GERP RS		5.1
Varity_R		0.17
gMVP		0.30

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: rs112813310; hg19: chr3-2613232;