19-44878273-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000252485.8(NECTIN2):c.1093G>A(p.Val365Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,143,934 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. V365V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 30)
  • Exomes 𝑓: 0.0038 (22 hom.)
• Consequence: NECTIN2 ENST00000252485.8 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.48

Genes affected

NECTIN2 (HGNC:9707): (nectin cell adhesion molecule 2) This gene encodes a single-pass type I membrane glycoprotein with two Ig-like C2-type domains and an Ig-like V-type domain. This protein is one of the plasma membrane components of adherens junctions. It also serves as an entry for certain mutant strains of herpes simplex virus and pseudorabies virus, and it is involved in cell to cell spreading of these viruses. Variations in this gene have been associated with differences in the severity of multiple sclerosis. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008009136).
• BP6: Variant 19-44878273-G-A is Benign according to our data. Variant chr19-44878273-G-A is described in ClinVar as [Benign]. Clinvar id is 2650089.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NECTIN2	NM_001042724.2	c.1042+3795G>A		intron_variant		ENST00000252483.10
NECTIN2	NM_002856.3	c.1093G>A	p.Val365Met	missense_variant	6/6
NECTIN2	XM_047439169.1	c.1043-280G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NECTIN2	ENST00000252485.8	c.1093G>A	p.Val365Met	missense_variant	6/6	1		A2
NECTIN2	ENST00000252483.10	c.1042+3795G>A		intron_variant		1	NM_001042724.2	P3
NECTIN2	ENST00000585601.1	c.85-100G>A		intron_variant		3
NECTIN2	ENST00000591581.1	c.565-280G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152056 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0119

Gnomad FIN AF: 0.00707

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00424 AC: 536 AN: 126314 Hom.: 6 AF XY: 0.00539 AC XY: 355 AN XY: 65854

Gnomad AFR exome AF: 0.000550

Gnomad AMR exome AF: 0.000850

Gnomad ASJ exome AF: 0.00244

Gnomad EAS exome AF: 0.0000909

Gnomad SAS exome AF: 0.0112

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.00343

Gnomad OTH exome AF: 0.00435

GnomAD4 exome AF: 0.00380 AC: 3773 AN: 991760 Hom.: 22 Cov.: 13 AF XY: 0.00414 AC XY: 2074 AN XY: 500868

Gnomad4 AFR exome AF: 0.000593

Gnomad4 AMR exome AF: 0.000611

Gnomad4 ASJ exome AF: 0.00250

Gnomad4 EAS exome AF: 0.0000591

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.00848

Gnomad4 NFE exome AF: 0.00328

Gnomad4 OTH exome AF: 0.00329

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152174 Hom.: 4 Cov.: 30 AF XY: 0.00317 AC XY: 236 AN XY: 74396

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0121

Gnomad4 FIN AF: 0.00707

Gnomad4 NFE AF: 0.00347

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00237 Hom.: 1

Bravo AF: 0.00189

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00163 AC: 6

ESP6500EA AF: 0.00294 AC: 21

ExAC AF: 0.00257 AC: 143

Asia WGS AF: 0.00289 AC: 10 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

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

NECTIN2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.15
Sift	Benign	0.054	T
Sift4G	Benign	0.084	T
Polyphen		0.86	P
Vest4		0.22
MVP		0.74
ClinPred		0.012	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs201037066; hg19: chr19-45381530; COSMIC: COSV52976950; COSMIC: COSV52976950;