2-124242203-C-T

Variant names:

• chr2-124242203-C-T
• rs1215232404
• NM_001367498.1:c.191C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001367498.1(CNTNAP5):​c.191C>T​(p.Thr64Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000568 in 1,583,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: CNTNAP5 NM_001367498.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92
• Publications: 0 publications found

Genes affected

CNTNAP5 (HGNC:18748): (contactin associated protein family member 5) This gene product belongs to the neurexin family, members of which function in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal growth factor repeats and laminin G domains. In addition, it includes an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, and thrombospondin N-terminal-like domains. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2672599).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP5	NM_001367498.1	c.191C>T	p.Thr64Ile	missense_variant	Exon 3 of 24	ENST00000682447.1	NP_001354427.1
CNTNAP5	NM_130773.4	c.191C>T	p.Thr64Ile	missense_variant	Exon 3 of 24		NP_570129.1
CNTNAP5	XM_017003316.2	c.191C>T	p.Thr64Ile	missense_variant	Exon 3 of 23		XP_016858805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP5	ENST00000682447.1	c.191C>T	p.Thr64Ile	missense_variant	Exon 3 of 24		NM_001367498.1	ENSP00000508115.1
CNTNAP5	ENST00000431078.1	c.191C>T	p.Thr64Ile	missense_variant	Exon 3 of 24	1		ENSP00000399013.1
CNTNAP5	ENST00000470921.1	n.109C>T		non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000244 AC: 5 AN: 204710 AF XY: 0.0000365

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000343

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000489 AC: 7 AN: 1431748 Hom.: 0 Cov.: 30 AF XY: 0.00000564 AC XY: 4 AN XY: 709338

African (AFR) AF: 0.00 AC: 0 AN: 32804

American (AMR) AF: 0.00 AC: 0 AN: 40108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.000183 AC: 7 AN: 38172

South Asian (SAS) AF: 0.00 AC: 0 AN: 82308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096222

Other (OTH) AF: 0.00 AC: 0 AN: 59346

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.191C>T (p.T64I) alteration is located in exon 3 (coding exon 3) of the CNTNAP5 gene. This alteration results from a C to T substitution at nucleotide position 191, causing the threonine (T) at amino acid position 64 to be replaced by an isoleucine (I). 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	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.071
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.27	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.1	L
PhyloP100		3.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.17	B
Vest4		0.20
MutPred		0.48		Loss of disorder (P = 0.0555);
MVP		0.58
MPC		0.29
ClinPred		0.28	T
GERP RS		3.5
Varity_R		0.19
gMVP		0.32
Mutation Taster		=91/9	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: rs1215232404; hg19: chr2-124999780;