9-39078737-G-C

Variant names:

• chr9-39078737-G-C
• rs1292174204
• NM_033655.5:c.3626C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_033655.5(CNTNAP3):​c.3626C>G​(p.Ser1209Cys) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 40)
  • Exomes 𝑓: 0.000037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNTNAP3 NM_033655.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35614157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP3	NM_033655.5	c.3626C>G	p.Ser1209Cys	missense_variant	Exon 22 of 24	ENST00000297668.11	NP_387504.2
CNTNAP3	NM_001393379.1	c.3383C>G	p.Ser1128Cys	missense_variant	Exon 21 of 23		NP_001380308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP3	ENST00000297668.11	c.3626C>G	p.Ser1209Cys	missense_variant	Exon 22 of 24	1	NM_033655.5	ENSP00000297668.6
CNTNAP3	ENST00000377656.6	c.3383C>G	p.Ser1128Cys	missense_variant	Exon 21 of 23	1		ENSP00000366884.2
CNTNAP3	ENST00000493965.5	n.274-281C>G		intron_variant	Intron 3 of 4	5
CNTNAP3	ENST00000477002.1	n.*81C>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152048 Hom.: 0 Cov.: 40

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000380

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 55356 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000372 AC: 50 AN: 1344806 Hom.: 0 Cov.: 83 AF XY: 0.0000393 AC XY: 26 AN XY: 661934

African (AFR) AF: 0.00 AC: 0 AN: 29186

American (AMR) AF: 0.00 AC: 0 AN: 23710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22780

East Asian (EAS) AF: 0.00 AC: 0 AN: 35350

South Asian (SAS) AF: 0.00 AC: 0 AN: 72466

European-Finnish (FIN) AF: 0.000242 AC: 9 AN: 37252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3836

European-Non Finnish (NFE) AF: 0.0000385 AC: 41 AN: 1064494

Other (OTH) AF: 0.00 AC: 0 AN: 55732

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000329 AC: 5 AN: 152048 Hom.: 0 Cov.: 40 AF XY: 0.0000404 AC XY: 3 AN XY: 74242

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000380 AC: 4 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3626C>G (p.S1209C) alteration is located in exon 22 (coding exon 22) of the CNTNAP3 gene. This alteration results from a C to G substitution at nucleotide position 3626, causing the serine (S) at amino acid position 1209 to be replaced by a cysteine (C). 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	Benign	0.30
BayesDel_addAF	Benign	-0.0064	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.052	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.59	T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		4.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.25
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.083	T;T
Polyphen		0.97	D;P
Vest4		0.13
MutPred		0.39		Loss of glycosylation at S1209 (P = 9e-04);.;
MVP		0.70
ClinPred		0.36	T
GERP RS		1.7
Varity_R		0.055
gMVP		0.34
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1292174204; hg19: chr9-39078734;