3-3042361-A-G

Variant names:

• chr3-3042361-A-G
• rs146888168
• NM_175607.3:c.2450A>G

Variant summary

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

The NM_175607.3(CNTN4):​c.2450A>G​(p.Asp817Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D817V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CNTN4 NM_175607.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.27
• Publications: 0 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-AS1 (HGNC:39985): (CNTN4 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175607.3. 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
	CNTN4	NM_175607.3	MANE Select	c.2450A>G	p.Asp817Gly	missense	Exon 21 of 25	NP_783200.1	Q8IWV2-1
	CNTN4	NM_001206955.2		c.2450A>G	p.Asp817Gly	missense	Exon 20 of 24	NP_001193884.1	Q8IWV2-1
	CNTN4	NM_001350095.2		c.2450A>G	p.Asp817Gly	missense	Exon 21 of 25	NP_001337024.1	Q8IWV2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN4	ENST00000418658.6	TSL:5 MANE Select	c.2450A>G	p.Asp817Gly	missense	Exon 21 of 25	ENSP00000396010.1	Q8IWV2-1
	CNTN4	ENST00000397459.6	TSL:1	c.1466A>G	p.Asp489Gly	missense	Exon 12 of 16	ENSP00000380600.2	Q8IWV2-4
	CNTN4	ENST00000484686.1	TSL:1	n.700A>G		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.54	P
Vest4		0.64
MutPred		0.46		Loss of stability (P = 0.0387)
MVP		0.74
MPC		0.14
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.73
gMVP		0.58
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs146888168; hg19: chr3-3084045;