rs9527026

Positions:

• chr13-33054102-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004795.4(KL):​c.1155G>A​(p.Lys385Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,613,384 control chromosomes in the GnomAD database, including 20,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1939 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18478 hom.)
• Consequence: KL NM_004795.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.370

Genes affected

KL (HGNC:6344): (klotho) This gene encodes a type-I membrane protein that is related to beta-glucosidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing and bone loss. [provided by RefSeq, Jul 2008]

KL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 13-33054102-G-A is Benign according to our data. Variant chr13-33054102-G-A is described in ClinVar as [Benign]. Clinvar id is 311692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KL	NM_004795.4	c.1155G>A	p.Lys385Lys	synonymous_variant	2/5	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.234G>A	p.Lys78Lys	synonymous_variant	2/5		XP_006719958.1
KL	XM_047430775.1	c.1155G>A	p.Lys385Lys	synonymous_variant	2/4		XP_047286731.1
KL	XM_047430776.1	c.1155G>A	p.Lys385Lys	synonymous_variant	2/4		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.1155G>A	p.Lys385Lys	synonymous_variant	2/5	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.1163G>A		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23661 AN: 151758 Hom.: 1938 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.141 AC: 35481 AN: 251310 Hom.: 2963 AF XY: 0.146 AC XY: 19872 AN XY: 135824

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.0734

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.176

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.154 AC: 225453 AN: 1461508 Hom.: 18478 Cov.: 34 AF XY: 0.155 AC XY: 112659 AN XY: 727060

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.0770

Gnomad4 ASJ exome AF: 0.208

Gnomad4 EAS exome AF: 0.000856

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.156 AC: 23674 AN: 151876 Hom.: 1939 Cov.: 32 AF XY: 0.157 AC XY: 11651 AN XY: 74208

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.216

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.148

Alfa AF: 0.158 Hom.: 1108

Bravo AF: 0.148

Asia WGS AF: 0.0750 AC: 264 AN: 3478

EpiCase AF: 0.154

EpiControl AF: 0.155

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Tumoral calcinosis, hyperphosphatemic, familial, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.1
DANN	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs9527026; hg19: chr13-33628239; COSMIC: COSV66309497;