rs2301708

Variant names:

• chr5-137634104-C-T
• rs2301708
• NM_017415.3:c.1383G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_017415.3(KLHL3):​c.1383G>A​(p.Glu461Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,898 control chromosomes in the GnomAD database, including 32,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2887 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29561 hom.)
• Consequence: KLHL3 NM_017415.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.972
• Publications: 19 publications found

Genes affected

KLHL3 (HGNC:6354): (kelch like family member 3) This gene is ubiquitously expressed and encodes a full-length protein which has an N-terminal BTB domain followed by a BACK domain and six kelch-like repeats in the C-terminus. These kelch-like repeats promote substrate ubiquitination of bound proteins via interaction of the BTB domain with the CUL3 (cullin 3) component of a cullin-RING E3 ubiquitin ligase (CRL) complex. Muatations in this gene cause pseudohypoaldosteronism type IID (PHA2D); a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Mar 2012]

KLHL3 Gene-Disease associations (from GenCC):

• pseudohypoaldosteronism type 2D

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 5-137634104-C-T is Benign according to our data. Variant chr5-137634104-C-T is described in ClinVar as Benign. ClinVar VariationId is 260807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.972 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017415.3. 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
	KLHL3	NM_017415.3	MANE Select	c.1383G>A	p.Glu461Glu	synonymous	Exon 12 of 15	NP_059111.2	Q9UH77-1
	KLHL3	NM_001257194.1		c.1287G>A	p.Glu429Glu	synonymous	Exon 12 of 15	NP_001244123.1	Q9UH77-2
	KLHL3	NM_001257195.2		c.1137G>A	p.Glu379Glu	synonymous	Exon 10 of 13	NP_001244124.1	Q9UH77-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL3	ENST00000309755.9	TSL:1 MANE Select	c.1383G>A	p.Glu461Glu	synonymous	Exon 12 of 15	ENSP00000312397.4	Q9UH77-1
	KLHL3	ENST00000508657.5	TSL:1	c.1287G>A	p.Glu429Glu	synonymous	Exon 12 of 15	ENSP00000422099.1	Q9UH77-2
	KLHL3	ENST00000506491.5	TSL:1	c.1137G>A	p.Glu379Glu	synonymous	Exon 10 of 13	ENSP00000424828.1	Q9UH77-3

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27140 AN: 152106 Hom.: 2890 Cov.: 33

Gnomad AFR AF: 0.0889

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.221 AC: 55610 AN: 251166 AF XY: 0.219

Gnomad AFR exome AF: 0.0849

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.432

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.196 AC: 286756 AN: 1461674 Hom.: 29561 Cov.: 33 AF XY: 0.197 AC XY: 143062 AN XY: 727138

African (AFR) AF: 0.0840 AC: 2813 AN: 33478

American (AMR) AF: 0.269 AC: 12037 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 4576 AN: 26128

East Asian (EAS) AF: 0.392 AC: 15548 AN: 39690

South Asian (SAS) AF: 0.237 AC: 20463 AN: 86232

European-Finnish (FIN) AF: 0.243 AC: 12968 AN: 53390

Middle Eastern (MID) AF: 0.100 AC: 574 AN: 5738

European-Non Finnish (NFE) AF: 0.186 AC: 206289 AN: 1111934

Other (OTH) AF: 0.190 AC: 11488 AN: 60384

GnomAD4 genome AF: 0.178 AC: 27152 AN: 152224 Hom.: 2887 Cov.: 33 AF XY: 0.187 AC XY: 13884 AN XY: 74422

African (AFR) AF: 0.0888 AC: 3689 AN: 41560

American (AMR) AF: 0.229 AC: 3508 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 625 AN: 3470

East Asian (EAS) AF: 0.407 AC: 2104 AN: 5174

South Asian (SAS) AF: 0.250 AC: 1208 AN: 4824

European-Finnish (FIN) AF: 0.266 AC: 2816 AN: 10596

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12756 AN: 67988

Other (OTH) AF: 0.175 AC: 369 AN: 2114

Alfa AF: 0.182 Hom.: 11601

Bravo AF: 0.172

Asia WGS AF: 0.298 AC: 1036 AN: 3478

EpiCase AF: 0.171

EpiControl AF: 0.172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant pseudohypoaldosteronism type 1 (1)
-	-	1	not specified (1)
-	-	1	Pseudohypoaldosteronism type 2D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	11
DANN	Benign	0.54
PhyloP100		0.97
Mutation Taster		=97/3	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: rs2301708; hg19: chr5-136969793; COSMIC: COSV59051876; COSMIC: COSV59051876;