9-39086768-C-G

Variant names:

• chr9-39086768-C-G
• rs753885289
• NM_033655.5:c.3302G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033655.5(CNTNAP3):​c.3302G>C​(p.Gly1101Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 151,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNTNAP3 NM_033655.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83
• Publications: 1 publications found

Genes affected

CNTNAP3 (HGNC:13834): (contactin associated protein family member 3) The protein encoded by this gene belongs to the NCP family of cell-recognition molecules. This family represents a distinct subgroup of the neurexins. NCP proteins mediate neuron-glial interactions in vertebrates and glial-glial contact in invertebrates. The protein encoded by this gene may play a role in cell recognition within the nervous system. Alternatively spliced transcript variants encoding different isoforms have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033655.5. 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
	CNTNAP3	NM_033655.5	MANE Select	c.3302G>C	p.Gly1101Ala	missense	Exon 20 of 24	NP_387504.2
	CNTNAP3	NM_001393379.1		c.3059G>C	p.Gly1020Ala	missense	Exon 19 of 23	NP_001380308.1	A6NC89

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP3	ENST00000297668.11	TSL:1 MANE Select	c.3302G>C	p.Gly1101Ala	missense	Exon 20 of 24	ENSP00000297668.6	Q9BZ76-1
	CNTNAP3	ENST00000377656.6	TSL:1	c.3059G>C	p.Gly1020Ala	missense	Exon 19 of 23	ENSP00000366884.2	A6NC89
	CNTNAP3	ENST00000865312.1		c.3422G>C	p.Gly1141Ala	missense	Exon 21 of 25	ENSP00000535371.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151160 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249954 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000315 AC: 46 AN: 1459574 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 726084

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4162

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111748

Other (OTH) AF: 0.0000166 AC: 1 AN: 60196

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151160 Hom.: 0 Cov.: 29 AF XY: 0.0000271 AC XY: 2 AN XY: 73678

African (AFR) AF: 0.00 AC: 0 AN: 41084

American (AMR) AF: 0.00 AC: 0 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67872

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.82
Sift	Benign	0.037	D
Sift4G	Uncertain	0.042	D
Polyphen		0.99	D
Vest4		0.80
MutPred		0.80		Loss of methylation at K1096 (P = 0.0926)
MVP		0.87
ClinPred		0.95	D
GERP RS		2.9
Varity_R		0.42
gMVP		0.66
Mutation Taster		=43/57	disease causing

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: rs753885289; hg19: chr9-39086765; COSMIC: COSV52665565; COSMIC: COSV52665565;