dbSNP rs650439: KL:c.2701+22T>A (chr13-33061802-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004795.4(KL):c.2701+22T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.841 in 1,609,134 control chromosomes in the GnomAD database, including 570,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 50275 hom., cov: 31)

Exomes 𝑓: 0.84 ( 520598 hom. )

Consequence

KL
NM_004795.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.97

Publications

27 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

KL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 13-33061802-T-A is Benign according to our data. Variant chr13-33061802-T-A is described in ClinVar as Benign. ClinVar VariationId is 1222763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004795.4. 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
	KL	NM_004795.4	MANE Select	c.2701+22T>A		intron	N/A	NP_004786.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	ENST00000380099.4	TSL:1 MANE Select	c.2701+22T>A		intron	N/A	ENSP00000369442.3	Q9UEF7-1
	KL	ENST00000487852.1	TSL:5	n.2759+22T>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.809

AC:

123066

AN:

152040

Hom.:

50237

Cov.:

show subpopulations

Gnomad AFR

AF:

0.726

Gnomad AMI

AF:

0.874

Gnomad AMR

AF:

0.812

Gnomad ASJ

AF:

0.913

Gnomad EAS

AF:

0.615

Gnomad SAS

AF:

0.803

Gnomad FIN

AF:

0.885

Gnomad MID

AF:

0.899

Gnomad NFE

AF:

0.856

Gnomad OTH

AF:

0.838

GnomAD2 exomes

AF:

0.819

AC:

200289

AN:

244550

AF XY:

0.823

show subpopulations

Gnomad AFR exome

AF:

0.725

Gnomad AMR exome

AF:

0.796

Gnomad ASJ exome

AF:

0.907

Gnomad EAS exome

AF:

0.602

Gnomad FIN exome

AF:

0.882

Gnomad NFE exome

AF:

0.857

Gnomad OTH exome

AF:

0.842

GnomAD4 exome

AF:

0.844

AC:

1229547

AN:

1456976

Hom.:

520598

Cov.:

AF XY:

0.844

AC XY:

611919

AN XY:

724878

show subpopulations

African (AFR)

AF:

0.725

AC:

24237

AN:

33444

American (AMR)

AF:

0.803

AC:

35910

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.910

AC:

23781

AN:

26126

East Asian (EAS)

AF:

0.627

AC:

24875

AN:

39684

South Asian (SAS)

AF:

0.815

AC:

70251

AN:

86190

European-Finnish (FIN)

AF:

0.882

AC:

43654

AN:

49472

Middle Eastern (MID)

AF:

0.854

AC:

4924

AN:

5768

European-Non Finnish (NFE)

AF:

0.856

AC:

951603

AN:

1111238

Other (OTH)

AF:

0.834

AC:

50312

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

9763

19525

29288

39050

48813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21128

42256

63384

84512

105640

<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:

0.809

AC:

123154

AN:

152158

Hom.:

50275

Cov.:

AF XY:

0.809

AC XY:

60155

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.726

AC:

30116

AN:

41492

American (AMR)

AF:

0.812

AC:

12411

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.913

AC:

3169

AN:

3472

East Asian (EAS)

AF:

0.615

AC:

3176

AN:

5162

South Asian (SAS)

AF:

0.803

AC:

3867

AN:

4814

European-Finnish (FIN)

AF:

0.885

AC:

9383

AN:

10604

Middle Eastern (MID)

AF:

0.901

AC:

265

AN:

294

European-Non Finnish (NFE)

AF:

0.856

AC:

58200

AN:

68002

Other (OTH)

AF:

0.837

AC:

1770

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1156

2312

3468

4624

5780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

874

1748

2622

3496

4370

<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:

0.840

Hom.:

9922

Bravo

AF:

0.803

Asia WGS

AF:

0.712

AC:

2479

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Tumoral calcinosis, hyperphosphatemic, familial, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.0020

(source)

DANN

Benign

0.51

PhyloP100

-2.0

Mutation Taster

=15/85

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over