chr19-44871907-C-T

Position:

• chr19-44871907-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001042724.2(NECTIN2):​c.533C>T​(p.Thr178Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,614,182 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (4 hom.)
• Consequence: NECTIN2 NM_001042724.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.00100

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051710606).
• BP6: Variant 19-44871907-C-T is Benign according to our data. Variant chr19-44871907-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3049638.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NECTIN2	NM_001042724.2	c.533C>T	p.Thr178Met	missense_variant	3/9	ENST00000252483.10	NP_001036189.1
NECTIN2	NM_002856.3	c.533C>T	p.Thr178Met	missense_variant	3/6		NP_002847.1
NECTIN2	XM_047439169.1	c.533C>T	p.Thr178Met	missense_variant	3/6		XP_047295125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NECTIN2	ENST00000252483.10	c.533C>T	p.Thr178Met	missense_variant	3/9	1	NM_001042724.2	ENSP00000252483	P3
NECTIN2	ENST00000252485.8	c.533C>T	p.Thr178Met	missense_variant	3/6	1		ENSP00000252485	A2
NECTIN2	ENST00000591581.1	c.56C>T	p.Thr19Met	missense_variant	1/4	2		ENSP00000465587

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 197 AN: 152182 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00134 AC: 337 AN: 250834 Hom.: 0 AF XY: 0.00132 AC XY: 179 AN XY: 135696

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00257

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00220 AC: 3221 AN: 1461882 Hom.: 4 Cov.: 32 AF XY: 0.00214 AC XY: 1554 AN XY: 727242

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00274

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152300 Hom.: 1 Cov.: 31 AF XY: 0.00102 AC XY: 76 AN XY: 74476

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00222 Hom.: 2

Bravo AF: 0.00156

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00219

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NECTIN2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2023

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	0.080
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.8
DANN	Benign	0.83
DEOGEN2	Benign	0.31	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.60	N;N
REVEL	Benign	0.056
Sift	Benign	0.037	D;T
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.0060	B;B
Vest4		0.13
MVP		0.068
MPC		0.41
ClinPred		0.0077	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.80

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: rs41290104; hg19: chr19-45375164;