3-2736142-T-C

Variant names:

• chr3-2736142-T-C
• rs143914533
• NM_175607.3:c.56-73T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_175607.3(CNTN4):​c.56-73T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.04 in 1,410,828 control chromosomes in the GnomAD database, including 1,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (92 hom., cov: 33)
  • Exomes 𝑓: 0.041 (1239 hom.)
• Consequence: CNTN4 NM_175607.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.764
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• autism spectrum disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-2736142-T-C is Benign according to our data. Variant chr3-2736142-T-C is described in ClinVar as [Benign]. Clinvar id is 1233350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0314 (4789/152314) while in subpopulation NFE AF = 0.0448 (3045/68026). AF 95% confidence interval is 0.0434. There are 92 homozygotes in GnomAd4. There are 2296 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4789 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN4	NM_175607.3	c.56-73T>C		intron_variant	Intron 4 of 24	ENST00000418658.6	NP_783200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTN4	ENST00000418658.6	c.56-73T>C		intron_variant	Intron 4 of 24	5	NM_175607.3	ENSP00000396010.1

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 4790 AN: 152196 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.00868

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0630

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0273

GnomAD4 exome AF: 0.0411 AC: 51685 AN: 1258514 Hom.: 1239 Cov.: 17 AF XY: 0.0409 AC XY: 26076 AN XY: 637030

African (AFR) AF: 0.00663 AC: 193 AN: 29106

American (AMR) AF: 0.0214 AC: 944 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 865 AN: 24560

East Asian (EAS) AF: 0.0172 AC: 658 AN: 38190

South Asian (SAS) AF: 0.0310 AC: 2535 AN: 81878

European-Finnish (FIN) AF: 0.0543 AC: 2846 AN: 52378

Middle Eastern (MID) AF: 0.0175 AC: 94 AN: 5384

European-Non Finnish (NFE) AF: 0.0448 AC: 41658 AN: 929596

Other (OTH) AF: 0.0355 AC: 1892 AN: 53358

GnomAD4 genome AF: 0.0314 AC: 4789 AN: 152314 Hom.: 92 Cov.: 33 AF XY: 0.0308 AC XY: 2296 AN XY: 74486

African (AFR) AF: 0.00787 AC: 327 AN: 41574

American (AMR) AF: 0.0249 AC: 381 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3470

East Asian (EAS) AF: 0.00870 AC: 45 AN: 5174

South Asian (SAS) AF: 0.0259 AC: 125 AN: 4830

European-Finnish (FIN) AF: 0.0630 AC: 669 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0448 AC: 3045 AN: 68026

Other (OTH) AF: 0.0270 AC: 57 AN: 2110

Alfa AF: 0.0439 Hom.: 190

Bravo AF: 0.0277

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.9
DANN	Benign	0.49
PhyloP100		0.76
Mutation Taster		=100/0	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: rs143914533; hg19: chr3-2777826;