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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP3	NM_033655.5	c.3302G>C	p.Gly1101Ala	missense_variant	Exon 20 of 24	ENST00000297668.11	NP_387504.2
CNTNAP3	NM_001393379.1	c.3059G>C	p.Gly1020Ala	missense_variant	Exon 19 of 23		NP_001380308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP3	ENST00000297668.11	c.3302G>C	p.Gly1101Ala	missense_variant	Exon 20 of 24	1	NM_033655.5	ENSP00000297668.6
CNTNAP3	ENST00000377656.6	c.3059G>C	p.Gly1020Ala	missense_variant	Exon 19 of 23	1		ENSP00000366884.2
CNTNAP3	ENST00000358144.6	c.3038G>C	p.Gly1013Ala	missense_variant	Exon 18 of 18	5		ENSP00000350863.2
CNTNAP3	ENST00000493965.5	n.133G>C		non_coding_transcript_exon_variant	Exon 2 of 5	5

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3302G>C (p.G1101A) alteration is located in exon 20 (coding exon 20) of the CNTNAP3 gene. This alteration results from a G to C substitution at nucleotide position 3302, causing the glycine (G) at amino acid position 1101 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.4	M;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.4	D;D;D
REVEL	Pathogenic	0.82
Sift	Benign	0.037	D;D;D
Sift4G	Uncertain	0.042	D;T;D
Polyphen		0.99	D;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;