9-39078740-G-A

Variant names:

• chr9-39078740-G-A
• rs191647909
• NM_033655.5:c.3623C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033655.5(CNTNAP3):​c.3623C>T​(p.Ala1208Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,489,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 40)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CNTNAP3 NM_033655.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06031671).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP3	NM_033655.5	c.3623C>T	p.Ala1208Val	missense_variant	Exon 22 of 24	ENST00000297668.11	NP_387504.2
CNTNAP3	NM_001393379.1	c.3380C>T	p.Ala1127Val	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.3623C>T	p.Ala1208Val	missense_variant	Exon 22 of 24	1	NM_033655.5	ENSP00000297668.6
CNTNAP3	ENST00000377656.6	c.3380C>T	p.Ala1127Val	missense_variant	Exon 21 of 23	1		ENSP00000366884.2
CNTNAP3	ENST00000493965.5	n.274-284C>T		intron_variant	Intron 3 of 4	5
CNTNAP3	ENST00000477002.1	n.*78C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000597 AC: 9 AN: 150798 Hom.: 0 Cov.: 40

Gnomad AFR AF: 0.000149

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000913 AC: 5 AN: 54774 AF XY: 0.00

Gnomad AFR exome AF: 0.000592

Gnomad AMR exome AF: 0.000112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000149

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000194 AC: 26 AN: 1338902 Hom.: 0 Cov.: 82 AF XY: 0.0000106 AC XY: 7 AN XY: 658592

African (AFR) AF: 0.000206 AC: 6 AN: 29094

American (AMR) AF: 0.000171 AC: 4 AN: 23370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22382

East Asian (EAS) AF: 0.0000283 AC: 1 AN: 35310

South Asian (SAS) AF: 0.0000140 AC: 1 AN: 71498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3824

European-Non Finnish (NFE) AF: 0.0000132 AC: 14 AN: 1061346

Other (OTH) AF: 0.00 AC: 0 AN: 55524

GnomAD4 genome AF: 0.0000596 AC: 9 AN: 150914 Hom.: 0 Cov.: 40 AF XY: 0.0000813 AC XY: 6 AN XY: 73792

African (AFR) AF: 0.000149 AC: 6 AN: 40374

American (AMR) AF: 0.00 AC: 0 AN: 15210

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5142

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

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3623C>T (p.A1208V) alteration is located in exon 22 (coding exon 22) of the CNTNAP3 gene. This alteration results from a C to T substitution at nucleotide position 3623, causing the alanine (A) at amino acid position 1208 to be replaced by a valine (V). 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	0.096
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.1
DANN	Benign	0.88
DEOGEN2	Benign	0.00088	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.50	T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.46	N;.
PhyloP100		1.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.17
Sift	Benign	0.28	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.47	P;P
Vest4		0.10
MVP		0.53
ClinPred		0.011	T
GERP RS		0.67
Varity_R		0.022
gMVP		0.30
Mutation Taster		=99/1	polymorphism

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: rs191647909; hg19: chr9-39078737;