2-124446771-T-C

Position:

• chr2-124446771-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001367498.1(CNTNAP5):​c.752T>C​(p.Leu251Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,613,702 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (9 hom.)
• Consequence: CNTNAP5 NM_001367498.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.46

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

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016334891).
• BP6: Variant 2-124446771-T-C is Benign according to our data. Variant chr2-124446771-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 778821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP5	NM_001367498.1	c.752T>C	p.Leu251Pro	missense_variant	6/24	ENST00000682447.1	NP_001354427.1
CNTNAP5	NM_130773.4	c.752T>C	p.Leu251Pro	missense_variant	6/24		NP_570129.1
CNTNAP5	XM_017003316.2	c.752T>C	p.Leu251Pro	missense_variant	6/23		XP_016858805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP5	ENST00000682447.1	c.752T>C	p.Leu251Pro	missense_variant	6/24		NM_001367498.1	ENSP00000508115.1
CNTNAP5	ENST00000431078.1	c.752T>C	p.Leu251Pro	missense_variant	6/24	1		ENSP00000399013.1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 310 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00202 AC: 500 AN: 247902 Hom.: 0 AF XY: 0.00208 AC XY: 280 AN XY: 134434

Gnomad AFR exome AF: 0.000840

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.000465

Gnomad NFE exome AF: 0.00333

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00296 AC: 4329 AN: 1461456 Hom.: 9 Cov.: 31 AF XY: 0.00296 AC XY: 2150 AN XY: 727014

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.000581

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74454

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00334

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00299 Hom.: 0

Bravo AF: 0.00208

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000933 AC: 4

ESP6500EA AF: 0.00363 AC: 31

ExAC AF: 0.00223 AC: 270

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00481

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	CNTNAP5: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

CNTNAP5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.55
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.12	N
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.28
Sift	Benign	0.39	T
Sift4G	Benign	0.25	T
Polyphen		0.79	P
Vest4		0.26
MVP		0.59
MPC		0.14
ClinPred		0.048	T
GERP RS		3.5
Varity_R		0.043
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs185130455; hg19: chr2-125204348;