rs2288775

Variant names:

• chr18-58316132-A-G
• rs2288775
• NM_001144967.3:c.348+100A>G

Your query was ambiguous. Multiple possible variants found:

• chr18-58316132-A-G
• chr18-58316132-A-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+100A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 973,444 control chromosomes in the GnomAD database, including 21,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5346 hom., cov: 32)
  • Exomes 𝑓: 0.19 (16467 hom.)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.283
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 18-58316132-A-G is Benign according to our data. Variant chr18-58316132-A-G is described in ClinVar as Benign. ClinVar VariationId is 1254207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.389 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	NM_001144967.3	MANE Select	c.348+100A>G		intron	N/A	NP_001138439.1	Q96PU5-1
	NEDD4L	NM_001437337.1		c.1185+100A>G		intron	N/A	NP_001424266.1	A0A1B0GVY1
	NEDD4L	NM_001144968.2		c.324+100A>G		intron	N/A	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.348+100A>G		intron	N/A	ENSP00000383199.2	Q96PU5-1
	NEDD4L	ENST00000357895.9	TSL:1	c.324+100A>G		intron	N/A	ENSP00000350569.4	Q96PU5-7
	NEDD4L	ENST00000382850.8	TSL:1	c.348+100A>G		intron	N/A	ENSP00000372301.3	Q96PU5-5

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37167 AN: 151958 Hom.: 5326 Cov.: 32

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.239

GnomAD4 exome AF: 0.192 AC: 157998 AN: 821366 Hom.: 16467 AF XY: 0.189 AC XY: 80770 AN XY: 426488

African (AFR) AF: 0.405 AC: 8340 AN: 20594

American (AMR) AF: 0.284 AC: 10684 AN: 37654

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 4952 AN: 19078

East Asian (EAS) AF: 0.269 AC: 9831 AN: 36594

South Asian (SAS) AF: 0.162 AC: 10402 AN: 64234

European-Finnish (FIN) AF: 0.114 AC: 5736 AN: 50462

Middle Eastern (MID) AF: 0.262 AC: 902 AN: 3438

European-Non Finnish (NFE) AF: 0.180 AC: 99064 AN: 550658

Other (OTH) AF: 0.209 AC: 8087 AN: 38654

GnomAD4 genome AF: 0.245 AC: 37234 AN: 152078 Hom.: 5346 Cov.: 32 AF XY: 0.240 AC XY: 17815 AN XY: 74334

African (AFR) AF: 0.394 AC: 16320 AN: 41460

American (AMR) AF: 0.244 AC: 3728 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 947 AN: 3468

East Asian (EAS) AF: 0.290 AC: 1496 AN: 5164

South Asian (SAS) AF: 0.156 AC: 752 AN: 4814

European-Finnish (FIN) AF: 0.110 AC: 1169 AN: 10594

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11958 AN: 67988

Other (OTH) AF: 0.244 AC: 515 AN: 2112

Alfa AF: 0.203 Hom.: 13283

Bravo AF: 0.266

Asia WGS AF: 0.274 AC: 951 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.9
DANN	Benign	0.72
PhyloP100		0.28
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: rs2288775; hg19: chr18-55983364; COSMIC: COSV56842844; COSMIC: COSV56842844;