Genetic Variant NECTIN1:n.1354G>A (chr11-119638121-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_203285.2(NECTIN1):c.1354G>A(p.Glu452Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

NECTIN1
NM_203285.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00900

Publications

1 publications found

Variant links:

Genes affected

NECTIN1 (HGNC:9706): (nectin cell adhesion molecule 1) This gene encodes an adhesion protein that plays a role in the organization of adherens junctions and tight junctions in epithelial and endothelial cells. The protein is a calcium(2+)-independent cell-cell adhesion molecule that belongs to the immunoglobulin superfamily and has 3 extracellular immunoglobulin-like loops, a single transmembrane domain (in some isoforms), and a cytoplasmic region. This protein acts as a receptor for glycoprotein D (gD) of herpes simplex viruses 1 and 2 (HSV-1, HSV-2), and pseudorabies virus (PRV) and mediates viral entry into epithelial and neuronal cells. Mutations in this gene cause cleft lip and palate/ectodermal dysplasia 1 syndrome (CLPED1) as well as non-syndromic cleft lip with or without cleft palate (CL/P). Alternative splicing results in multiple transcript variants encoding proteins with distinct C-termini. [provided by RefSeq, Oct 2009]

NECTIN1 links:

USP2-AS1 (HGNC:48673): (USP2 antisense RNA 1)

USP2-AS1 links:

LOC105369520 (HGNC:):

LOC105369520 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04911375).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203285.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NECTIN1	NM_203285.2		c.1354G>A	p.Glu452Lys	missense	Exon 8 of 8	NP_976030.1	Q15223-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NECTIN1	ENST00000341398.6	TSL:1	n.1354G>A	non_coding_transcript_exon	Exon 8 of 8
NECTIN1	ENST00000531468.2	TSL:3	c.1341+13G>A	intron	N/A	ENSP00000513010.1	A0A8V8TKI1
USP2-AS1	ENST00000706364.1		n.514+744C>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000483

AC:

AN:

248698

AF XY:

0.0000371

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461188

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726842

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33462

American (AMR)

AF:

0.0000896

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.000202

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000465

AC:

AN:

86062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111784

Other (OTH)

AF:

0.0000166

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41406

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.9

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.40

M_CAP

Benign

0.047

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.73

PhyloP100

-0.0090

PROVEAN

Benign

-1.1

REVEL

Benign

0.076

Sift

Pathogenic

0.0

Sift4G

Benign

0.069

Polyphen

0.0010

Vest4

0.13

MutPred

0.21

Gain of methylation at E452 (P = 0.0051)

MVP

0.043

ClinPred

0.11

GERP RS

1.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over