chr18-58316098-T-C

Variant names:

• chr18-58316098-T-C
• rs2288774
• NM_001144967.3:c.348+66T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001144967.3(NEDD4L):​c.348+66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 1,288,724 control chromosomes in the GnomAD database, including 149,735 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20911 hom., cov: 31)
  • Exomes 𝑓: 0.47 (128824 hom.)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.642
• Publications: 34 publications found

Genes affected

NEDD4L (HGNC:7728): (NEDD4 like E3 ubiquitin protein ligase) This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC. Single nucleotide polymorphisms in this gene may be associated with essential hypertension. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

NEDD4L Gene-Disease associations (from GenCC):

• periventricular nodular heterotopia 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-58316098-T-C is Benign according to our data. Variant chr18-58316098-T-C is described in ClinVar as Benign. ClinVar VariationId is 1235847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144967.3. 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
	NEDD4L	NM_001144967.3	MANE Select	c.348+66T>C		intron	N/A	NP_001138439.1
	NEDD4L	NM_001437337.1		c.1185+66T>C		intron	N/A	NP_001424266.1
	NEDD4L	NM_001144968.2		c.324+66T>C		intron	N/A	NP_001138440.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.348+66T>C		intron	N/A	ENSP00000383199.2
	NEDD4L	ENST00000357895.9	TSL:1	c.324+66T>C		intron	N/A	ENSP00000350569.4
	NEDD4L	ENST00000382850.8	TSL:1	c.348+66T>C		intron	N/A	ENSP00000372301.3

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78764 AN: 151840 Hom.: 20862 Cov.: 31

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.534

GnomAD4 exome AF: 0.471 AC: 534914 AN: 1136766 Hom.: 128824 AF XY: 0.467 AC XY: 270574 AN XY: 579124

African (AFR) AF: 0.646 AC: 17248 AN: 26712

American (AMR) AF: 0.479 AC: 20023 AN: 41790

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 13726 AN: 23232

East Asian (EAS) AF: 0.381 AC: 14500 AN: 38070

South Asian (SAS) AF: 0.391 AC: 30354 AN: 77682

European-Finnish (FIN) AF: 0.490 AC: 25827 AN: 52684

Middle Eastern (MID) AF: 0.615 AC: 2996 AN: 4874

European-Non Finnish (NFE) AF: 0.469 AC: 386040 AN: 822386

Other (OTH) AF: 0.491 AC: 24200 AN: 49336

GnomAD4 genome AF: 0.519 AC: 78867 AN: 151958 Hom.: 20911 Cov.: 31 AF XY: 0.516 AC XY: 38362 AN XY: 74276

African (AFR) AF: 0.630 AC: 26092 AN: 41422

American (AMR) AF: 0.491 AC: 7512 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2122 AN: 3466

East Asian (EAS) AF: 0.381 AC: 1969 AN: 5168

South Asian (SAS) AF: 0.372 AC: 1787 AN: 4802

European-Finnish (FIN) AF: 0.504 AC: 5321 AN: 10552

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32246 AN: 67946

Other (OTH) AF: 0.538 AC: 1135 AN: 2110

Alfa AF: 0.500 Hom.: 44740

Bravo AF: 0.528

Asia WGS AF: 0.438 AC: 1524 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.56
DANN	Benign	0.34
PhyloP100		-0.64
Mutation Taster		=100/0	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: rs2288774; hg19: chr18-55983330; COSMIC: COSV56842276; COSMIC: COSV56842276;