2-124025730-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001367498.1(CNTNAP5):c.80A>C(p.Asn27Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00058 in 1,611,698 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (8 hom.)
• Consequence: CNTNAP5 NM_001367498.1 missense, splice_region
• Scores: Splicing: ADA: 0.0002974
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.68

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008075684).
• BP6: Variant 2-124025730-A-C is Benign according to our data. Variant chr2-124025730-A-C is described in ClinVar as [Benign]. Clinvar id is 780098.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000645 (98/151994) while in subpopulation EAS AF= 0.0189 (97/5122). AF 95% confidence interval is 0.0159. There are 1 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP5	NM_001367498.1	c.80A>C	p.Asn27Thr	missense_variant, splice_region_variant	1/24	ENST00000682447.1
CNTNAP5	NM_130773.4	c.80A>C	p.Asn27Thr	missense_variant, splice_region_variant	1/24
CNTNAP5	XM_017003316.2	c.80A>C	p.Asn27Thr	missense_variant, splice_region_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP5	ENST00000682447.1	c.80A>C	p.Asn27Thr	missense_variant, splice_region_variant	1/24		NM_001367498.1	A1
CNTNAP5	ENST00000431078.1	c.80A>C	p.Asn27Thr	missense_variant, splice_region_variant	1/24	1		P4
CNTNAP5	ENST00000423939.2	n.444A>C		splice_region_variant, non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.000652 AC: 99 AN: 151876 Hom.: 1 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: 0.0191

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00139 AC: 346 AN: 248686 Hom.: 5 AF XY: 0.00134 AC XY: 181 AN XY: 134930

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0189

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000573 AC: 836 AN: 1459704 Hom.: 8 Cov.: 29 AF XY: 0.000570 AC XY: 414 AN XY: 726250

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0204

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000332

GnomAD4 genome AF: 0.000645 AC: 98 AN: 151994 Hom.: 1 Cov.: 32 AF XY: 0.000861 AC XY: 64 AN XY: 74298

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0189

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000806 Hom.: 0

Bravo AF: 0.000669

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00134 AC: 162

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	20
Dann	Benign	0.76
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.27
Sift	Benign	0.11	T
Sift4G	Benign	0.25	T
Polyphen		0.0030	B
Vest4		0.42
MVP		0.62
MPC		0.088
ClinPred		0.035	T
GERP RS		4.3
Varity_R		0.085
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.060		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: rs117021222; hg19: chr2-124783307;