11-119664967-CCCTCCTCCTCCT-CCCTCCTCCTCCTCCT

Variant names:

• chr11-119664967-C-CCCT
• rs137909701
• NM_002855.5:c.1331_1333dupAGG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_002855.5(NECTIN1):​c.1331_1333dupAGG​(p.Glu444dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0781 in 1,610,534 control chromosomes in the GnomAD database, including 4,396 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (394 hom., cov: 31)
  • Exomes 𝑓: 0.080 (4002 hom.)
• Consequence: NECTIN1 NM_002855.5 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• cleft lip/palate-ectodermal dysplasia syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_002855.5
• BP6: Variant 11-119664967-C-CCCT is Benign according to our data. Variant chr11-119664967-C-CCCT is described in ClinVar as Benign. ClinVar VariationId is 218617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0905 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002855.5. 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_002855.5	MANE Select	c.1331_1333dupAGG	p.Glu444dup	conservative_inframe_insertion	Exon 6 of 6	NP_002846.3
	NECTIN1	NM_203285.2		c.1003+10189_1003+10191dupAGG		intron	N/A	NP_976030.1	Q15223-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NECTIN1	ENST00000264025.8	TSL:1 MANE Select	c.1331_1333dupAGG	p.Glu444dup	conservative_inframe_insertion	Exon 6 of 6	ENSP00000264025.3	Q15223-1
	NECTIN1	ENST00000341398.6	TSL:1	n.1003+10189_1003+10191dupAGG		intron	N/A
	NECTIN1	ENST00000531468.2	TSL:3	c.1003+10189_1003+10191dupAGG		intron	N/A	ENSP00000513010.1	A0A8V8TKI1

Frequencies

GnomAD3 genomes AF: 0.0587 AC: 8900 AN: 151530 Hom.: 394 Cov.: 31

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.0477

Gnomad SAS AF: 0.0177

Gnomad FIN AF: 0.0817

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0924

Gnomad OTH AF: 0.0448

GnomAD2 exomes AF: 0.0626 AC: 14437 AN: 230564 AF XY: 0.0632

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.0484

Gnomad FIN exome AF: 0.0865

Gnomad NFE exome AF: 0.0925

Gnomad OTH exome AF: 0.0689

GnomAD4 exome AF: 0.0801 AC: 116885 AN: 1458888 Hom.: 4002 Cov.: 39 AF XY: 0.0783 AC XY: 56821 AN XY: 725744

African (AFR) AF: 0.0134 AC: 447 AN: 33368

American (AMR) AF: 0.0277 AC: 1236 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 607 AN: 26096

East Asian (EAS) AF: 0.0343 AC: 1361 AN: 39670

South Asian (SAS) AF: 0.0193 AC: 1666 AN: 86186

European-Finnish (FIN) AF: 0.0841 AC: 4463 AN: 53088

Middle Eastern (MID) AF: 0.0226 AC: 130 AN: 5758

European-Non Finnish (NFE) AF: 0.0928 AC: 102956 AN: 1109808

Other (OTH) AF: 0.0667 AC: 4019 AN: 60268

GnomAD4 genome AF: 0.0587 AC: 8905 AN: 151646 Hom.: 394 Cov.: 31 AF XY: 0.0576 AC XY: 4269 AN XY: 74086

African (AFR) AF: 0.0158 AC: 653 AN: 41398

American (AMR) AF: 0.0339 AC: 516 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3462

East Asian (EAS) AF: 0.0476 AC: 245 AN: 5148

South Asian (SAS) AF: 0.0186 AC: 89 AN: 4794

European-Finnish (FIN) AF: 0.0817 AC: 859 AN: 10518

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0924 AC: 6264 AN: 67792

Other (OTH) AF: 0.0448 AC: 94 AN: 2096

Alfa AF: 0.0377 Hom.: 43

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cleft lip/palate-ectodermal dysplasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=76/24	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs137909701; hg19: chr11-119535677; COSMIC: COSV50601650;