3-2735938-A-G

Variant names:

• chr3-2735938-A-G
• rs1554198
• NM_175607.3:c.56-277A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175607.3(CNTN4):​c.56-277A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 559,134 control chromosomes in the GnomAD database, including 217,878 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (51747 hom., cov: 29)
  • Exomes 𝑓: 0.90 (166131 hom.)
• Consequence: CNTN4 NM_175607.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.509
• Publications: 4 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=-0.96).
• BP6: Variant 3-2735938-A-G is Benign according to our data. Variant chr3-2735938-A-G is described in ClinVar as [Benign]. Clinvar id is 1272604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN4	NM_175607.3	c.56-277A>G		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.56-277A>G		intron_variant	Intron 4 of 24	5	NM_175607.3	ENSP00000396010.1

Frequencies

GnomAD3 genomes AF: 0.805 AC: 121990 AN: 151626 Hom.: 51733 Cov.: 29

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.938

Gnomad AMR AF: 0.895

Gnomad ASJ AF: 0.885

Gnomad EAS AF: 0.872

Gnomad SAS AF: 0.835

Gnomad FIN AF: 0.871

Gnomad MID AF: 0.790

Gnomad NFE AF: 0.939

Gnomad OTH AF: 0.831

GnomAD2 exomes AF: 0.885 AC: 190962 AN: 215884 AF XY: 0.887

Gnomad AFR exome AF: 0.495

Gnomad AMR exome AF: 0.937

Gnomad ASJ exome AF: 0.881

Gnomad EAS exome AF: 0.854

Gnomad FIN exome AF: 0.876

Gnomad NFE exome AF: 0.939

Gnomad OTH exome AF: 0.902

GnomAD4 exome AF: 0.899 AC: 366167 AN: 407390 Hom.: 166131 Cov.: 2 AF XY: 0.897 AC XY: 206016 AN XY: 229754

African (AFR) AF: 0.499 AC: 6178 AN: 12384

American (AMR) AF: 0.935 AC: 34211 AN: 36594

Ashkenazi Jewish (ASJ) AF: 0.885 AC: 12229 AN: 13816

East Asian (EAS) AF: 0.871 AC: 15051 AN: 17282

South Asian (SAS) AF: 0.839 AC: 54960 AN: 65506

European-Finnish (FIN) AF: 0.882 AC: 16377 AN: 18560

Middle Eastern (MID) AF: 0.784 AC: 2454 AN: 3130

European-Non Finnish (NFE) AF: 0.940 AC: 207055 AN: 220174

Other (OTH) AF: 0.885 AC: 17652 AN: 19944

GnomAD4 genome AF: 0.804 AC: 122040 AN: 151744 Hom.: 51747 Cov.: 29 AF XY: 0.804 AC XY: 59559 AN XY: 74112

African (AFR) AF: 0.508 AC: 20999 AN: 41300

American (AMR) AF: 0.895 AC: 13654 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.885 AC: 3074 AN: 3472

East Asian (EAS) AF: 0.871 AC: 4460 AN: 5118

South Asian (SAS) AF: 0.835 AC: 4005 AN: 4798

European-Finnish (FIN) AF: 0.871 AC: 9146 AN: 10502

Middle Eastern (MID) AF: 0.781 AC: 228 AN: 292

European-Non Finnish (NFE) AF: 0.939 AC: 63865 AN: 67988

Other (OTH) AF: 0.833 AC: 1754 AN: 2106

Alfa AF: 0.882 Hom.: 25382

Bravo AF: 0.794

Asia WGS AF: 0.824 AC: 2868 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

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	-0.96
CADD	Benign	1.3
DANN	Benign	0.29
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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: rs1554198; hg19: chr3-2777622;