rs12964776

Variant names:

• chr18-58390748-C-T
• rs12964776
• NM_001144967.3:c.2752+6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001144967.3(NEDD4L):​c.2752+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,573,436 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.013 (190 hom.)
• Consequence: NEDD4L NM_001144967.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001561
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.405
• Publications: 5 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=-0.59).
• BP6: Variant 18-58390748-C-T is Benign according to our data. Variant chr18-58390748-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.011 (1668/152240) while in subpopulation SAS AF = 0.032 (154/4816). AF 95% confidence interval is 0.0279. There are 17 homozygotes in GnomAd4. There are 876 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1668 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.2752+6C>T		splice_region intron	N/A	NP_001138439.1	Q96PU5-1
	NEDD4L	NM_001437337.1		c.3589+6C>T		splice_region intron	N/A	NP_001424266.1	A0A1B0GVY1
	NEDD4L	NM_001144968.2		c.2728+6C>T		splice_region 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.2752+6C>T		splice_region intron	N/A	ENSP00000383199.2	Q96PU5-1
	NEDD4L	ENST00000357895.9	TSL:1	c.2728+6C>T		splice_region intron	N/A	ENSP00000350569.4	Q96PU5-7
	NEDD4L	ENST00000382850.8	TSL:1	c.2692+6C>T		splice_region intron	N/A	ENSP00000372301.3	Q96PU5-5

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1669 AN: 152122 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0322

Gnomad FIN AF: 0.0286

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0139 AC: 2810 AN: 202232 AF XY: 0.0153

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00381

Gnomad ASJ exome AF: 0.00888

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0133 AC: 18966 AN: 1421196 Hom.: 190 Cov.: 26 AF XY: 0.0142 AC XY: 9980 AN XY: 704514

African (AFR) AF: 0.00125 AC: 41 AN: 32838

American (AMR) AF: 0.00432 AC: 176 AN: 40774

Ashkenazi Jewish (ASJ) AF: 0.00886 AC: 226 AN: 25508

East Asian (EAS) AF: 0.00 AC: 0 AN: 38566

South Asian (SAS) AF: 0.0340 AC: 2772 AN: 81514

European-Finnish (FIN) AF: 0.0295 AC: 1521 AN: 51584

Middle Eastern (MID) AF: 0.0160 AC: 91 AN: 5702

European-Non Finnish (NFE) AF: 0.0124 AC: 13458 AN: 1085742

Other (OTH) AF: 0.0115 AC: 681 AN: 58968

GnomAD4 genome AF: 0.0110 AC: 1668 AN: 152240 Hom.: 17 Cov.: 32 AF XY: 0.0118 AC XY: 876 AN XY: 74438

African (AFR) AF: 0.00245 AC: 102 AN: 41554

American (AMR) AF: 0.00294 AC: 45 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.0320 AC: 154 AN: 4816

European-Finnish (FIN) AF: 0.0286 AC: 303 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0133 AC: 902 AN: 68014

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0110 Hom.: 7

Bravo AF: 0.00796

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	NEDD4L-related disorder (1)
-	-	1	not specified (1)
-	-	1	Periventricular nodular heterotopia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.73
PhyloP100		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.030
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: rs12964776; hg19: chr18-56057980;