13-33060846-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.708

Publications

46 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

tumoral calcinosis, hyperphosphatemic, familial, 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tumoral calcinosis, hyperphosphatemic, familial, 3
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

KL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 311698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
KL	NM_004795.4 link	c.1767C>T	p.His589His	synonymous_variant	Exon 4 of 5	ENST00000380099.4	NP_004786.2	Q9UEF7-1
KL	XM_006719895.3 link	c.846C>T	p.His282His	synonymous_variant	Exon 4 of 5		XP_006719958.1
KL	XM_047430776.1 link	c.*167C>T		3_prime_UTR_variant	Exon 4 of 4		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4 link	c.1767C>T	p.His589His	synonymous_variant	Exon 4 of 5	1	NM_004795.4	ENSP00000369442.3		Q9UEF7-1
KL	ENST00000487852.1 link	n.1825C>T		non_coding_transcript_exon_variant	Exon 4 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.311

AC:

47244

AN:

152056

Hom.:

9085

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.375

AC:

94398

AN:

251476

AF XY:

0.375

show subpopulations

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 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.:

AF XY:

0.387

AC XY:

281682

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0800

AC:

2677

AN:

33480

American (AMR)

AF:

0.537

AC:

24023

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.428

AC:

11194

AN:

26136

East Asian (EAS)

AF:

0.166

AC:

6604

AN:

39700

South Asian (SAS)

AF:

0.344

AC:

29668

AN:

86258

European-Finnish (FIN)

AF:

0.383

AC:

20470

AN:

53420

Middle Eastern (MID)

AF:

0.400

AC:

2307

AN:

5768

European-Non Finnish (NFE)

AF:

0.403

AC:

447579

AN:

1111962

Other (OTH)

AF:

0.367

AC:

22139

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

21836

43672

65507

87343

109179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13666

27332

40998

54664

68330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.311

AC:

47265

AN:

152174

Hom.:

9096

Cov.:

AF XY:

0.310

AC XY:

23066

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0897

AC:

3726

AN:

41546

American (AMR)

AF:

0.460

AC:

7030

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.426

AC:

1479

AN:

3472

East Asian (EAS)

AF:

0.169

AC:

874

AN:

5162

South Asian (SAS)

AF:

0.315

AC:

1519

AN:

4824

European-Finnish (FIN)

AF:

0.380

AC:

4021

AN:

10578

Middle Eastern (MID)

AF:

0.425

AC:

125

AN:

294

European-Non Finnish (NFE)

AF:

0.403

AC:

27381

AN:

67982

Other (OTH)

AF:

0.350

AC:

739

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1538

3075

4613

6150

7688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

462

924

1386

1848

2310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.343

Hom.:

4998

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

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Tumoral calcinosis, hyperphosphatemic, familial, 3

Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

-0.83

CADD

Benign

0.63

(source)

DANN

Benign

0.31

PhyloP100

-0.71

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over