13-33060846-C-T

Position:

• chr13-33060846-C-T

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.1767C>T​(p.His589His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,614,016 control chromosomes in the GnomAD database, including 122,702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9096 hom., cov: 33)
  • Exomes 𝑓: 0.39 (113606 hom.)
• Consequence: KL NM_004795.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.708

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-33060846-C-T is Benign according to our data. Variant chr13-33060846-C-T is described in ClinVar as [Benign]. Clinvar id is 311698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-33060846-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.708 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KL	NM_004795.4	c.1767C>T	p.His589His	synonymous_variant	4/5	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.846C>T	p.His282His	synonymous_variant	4/5		XP_006719958.1
KL	XM_047430776.1	c.*167C>T		3_prime_UTR_variant	4/4		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.1767C>T	p.His589His	synonymous_variant	4/5	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.1825C>T		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47244 AN: 152056 Hom.: 9085 Cov.: 33

Gnomad AFR AF: 0.0899

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.346

GnomAD3 exomes AF: 0.375 AC: 94398 AN: 251476 Hom.: 19633 AF XY: 0.375 AC XY: 50960 AN XY: 135910

Gnomad AFR exome AF: 0.0792

Gnomad AMR exome AF: 0.542

Gnomad ASJ exome AF: 0.429

Gnomad EAS exome AF: 0.155

Gnomad SAS exome AF: 0.342

Gnomad FIN exome AF: 0.377

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.402

GnomAD4 exome AF: 0.388 AC: 566661 AN: 1461842 Hom.: 113606 Cov.: 58 AF XY: 0.387 AC XY: 281682 AN XY: 727222

Gnomad4 AFR exome AF: 0.0800

Gnomad4 AMR exome AF: 0.537

Gnomad4 ASJ exome AF: 0.428

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.344

Gnomad4 FIN exome AF: 0.383

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.367

GnomAD4 genome AF: 0.311 AC: 47265 AN: 152174 Hom.: 9096 Cov.: 33 AF XY: 0.310 AC XY: 23066 AN XY: 74406

Gnomad4 AFR AF: 0.0897

Gnomad4 AMR AF: 0.460

Gnomad4 ASJ AF: 0.426

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.315

Gnomad4 FIN AF: 0.380

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.350

Alfa AF: 0.324 Hom.: 3278

Bravo AF: 0.310

Asia WGS AF: 0.274 AC: 955 AN: 3478

EpiCase AF: 0.408

EpiControl AF: 0.404

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Tumoral calcinosis, hyperphosphatemic, familial, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.63
DANN	Benign	0.31

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: rs564481; hg19: chr13-33634983; COSMIC: COSV66308637;