rs202008394

Variant names:

• chr18-58325121-C-T
• rs202008394
• NM_001144967.3:c.639C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001144967.3(NEDD4L):​c.639C>T​(p.Asn213Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.000657 in 1,614,032 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: NEDD4L NM_001144967.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.85
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 18-58325121-C-T is Benign according to our data. Variant chr18-58325121-C-T is described in ClinVar as Benign. ClinVar VariationId is 241028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 73 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	NM_001144967.3	MANE Select	c.639C>T	p.Asn213Asn	synonymous	Exon 9 of 31	NP_001138439.1	Q96PU5-1
	NEDD4L	NM_001437337.1		c.1476C>T	p.Asn492Asn	synonymous	Exon 5 of 27	NP_001424266.1	A0A1B0GVY1
	NEDD4L	NM_001144968.2		c.615C>T	p.Asn205Asn	synonymous	Exon 9 of 31	NP_001138440.1	Q96PU5-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.639C>T	p.Asn213Asn	synonymous	Exon 9 of 31	ENSP00000383199.2	Q96PU5-1
	NEDD4L	ENST00000357895.9	TSL:1	c.615C>T	p.Asn205Asn	synonymous	Exon 9 of 31	ENSP00000350569.4	Q96PU5-7
	NEDD4L	ENST00000382850.8	TSL:1	c.639C>T	p.Asn213Asn	synonymous	Exon 9 of 30	ENSP00000372301.3	Q96PU5-5

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000529 AC: 132 AN: 249300 AF XY: 0.000547

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000832

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000676 AC: 988 AN: 1461690 Hom.: 1 Cov.: 31 AF XY: 0.000652 AC XY: 474 AN XY: 727122

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.000787 AC: 875 AN: 1111864

Other (OTH) AF: 0.000795 AC: 48 AN: 60372

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74506

African (AFR) AF: 0.0000962 AC: 4 AN: 41582

American (AMR) AF: 0.000849 AC: 13 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000503 Hom.: 0

Bravo AF: 0.000552

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=66/34	polymorphism

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: rs202008394; hg19: chr18-55992353;