2-124903032-C-T

Variant names:

• chr2-124903032-C-T
• rs34165507
• NM_001367498.1:c.3587C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001367498.1(CNTNAP5):​c.3587C>T​(p.Thr1196Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,607,612 control chromosomes in the GnomAD database, including 393 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (32 hom., cov: 32)
  • Exomes 𝑓: 0.021 (361 hom.)
• Consequence: CNTNAP5 NM_001367498.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0740
• Publications: 10 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028316975).
• BP6: Variant 2-124903032-C-T is Benign according to our data. Variant chr2-124903032-C-T is described in ClinVar as Benign. ClinVar VariationId is 3056415.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.015 (2287/152216) while in subpopulation NFE AF = 0.0235 (1597/67994). AF 95% confidence interval is 0.0225. There are 32 homozygotes in GnomAd4. There are 1003 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367498.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP5	NM_001367498.1	MANE Select	c.3587C>T	p.Thr1196Met	missense	Exon 22 of 24	NP_001354427.1
	CNTNAP5	NM_130773.4		c.3584C>T	p.Thr1195Met	missense	Exon 22 of 24	NP_570129.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP5	ENST00000682447.1	MANE Select	c.3587C>T	p.Thr1196Met	missense	Exon 22 of 24	ENSP00000508115.1
	CNTNAP5	ENST00000431078.1	TSL:1	c.3584C>T	p.Thr1195Met	missense	Exon 22 of 24	ENSP00000399013.1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2285 AN: 152098 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00613

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0154 AC: 3661 AN: 237804 AF XY: 0.0165

Gnomad AFR exome AF: 0.00516

Gnomad AMR exome AF: 0.00891

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.00443

Gnomad NFE exome AF: 0.0222

Gnomad OTH exome AF: 0.0204

GnomAD4 exome AF: 0.0208 AC: 30229 AN: 1455396 Hom.: 361 Cov.: 31 AF XY: 0.0210 AC XY: 15164 AN XY: 723376

African (AFR) AF: 0.00434 AC: 145 AN: 33386

American (AMR) AF: 0.00981 AC: 431 AN: 43916

Ashkenazi Jewish (ASJ) AF: 0.0263 AC: 683 AN: 25982

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39274

South Asian (SAS) AF: 0.0164 AC: 1397 AN: 85154

European-Finnish (FIN) AF: 0.00501 AC: 266 AN: 53052

Middle Eastern (MID) AF: 0.0203 AC: 117 AN: 5756

European-Non Finnish (NFE) AF: 0.0235 AC: 26034 AN: 1108732

Other (OTH) AF: 0.0192 AC: 1154 AN: 60144

GnomAD4 genome AF: 0.0150 AC: 2287 AN: 152216 Hom.: 32 Cov.: 32 AF XY: 0.0135 AC XY: 1003 AN XY: 74422

African (AFR) AF: 0.00611 AC: 254 AN: 41556

American (AMR) AF: 0.0116 AC: 177 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5150

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4828

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1597 AN: 67994

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.0199 Hom.: 106

Bravo AF: 0.0155

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0244 AC: 94

ESP6500AA AF: 0.00518 AC: 22

ESP6500EA AF: 0.0243 AC: 207

ExAC AF: 0.0148 AC: 1790

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CNTNAP5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	3.8
DANN	Benign	0.95
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-0.074
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.23
Sift	Benign	0.039	D
Sift4G	Uncertain	0.031	D
Polyphen		0.0050	B
Vest4		0.052
MPC		0.088
ClinPred		0.015	T
GERP RS		-5.5
Varity_R		0.028
gMVP		0.40
Mutation Taster		=91/9	polymorphism (auto)

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: rs34165507; hg19: chr2-125660609; COSMIC: COSV99081551;