Genetic Variant KL:p.Pro2Ser (chr13-33016444-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004795.4(KL):c.4C>T(p.Pro2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 959,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

KL
NM_004795.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.02

Publications

2 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:

LOC124903151 (HGNC:):

LOC124903151 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11635697).

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.4C>T	p.Pro2Ser	missense	Exon 1 of 5	NP_004786.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KL	ENST00000380099.4	TSL:1 MANE Select	c.4C>T	p.Pro2Ser	missense	Exon 1 of 5	ENSP00000369442.3	Q9UEF7-1
KL	ENST00000487852.1	TSL:5	n.12C>T		non_coding_transcript_exon	Exon 1 of 5
ENSG00000308044	ENST00000830674.1		n.-200G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000700

AC:

AN:

142924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000216

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000318

AC:

AN:

816410

Hom.:

Cov.:

AF XY:

0.0000370

AC XY:

AN XY:

378266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15462

American (AMR)

AF:

0.00

AC:

AN:

1124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5134

East Asian (EAS)

AF:

0.00

AC:

AN:

3688

South Asian (SAS)

AF:

0.000773

AC:

AN:

16820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1602

European-Non Finnish (NFE)

AF:

0.0000161

AC:

AN:

744968

Other (OTH)

AF:

0.0000372

AC:

AN:

26872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000700

AC:

AN:

142924

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

69390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40328

American (AMR)

AF:

0.00

AC:

AN:

14556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3316

East Asian (EAS)

AF:

0.00

AC:

AN:

4764

South Asian (SAS)

AF:

0.000216

AC:

AN:

4628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64488

Other (OTH)

AF:

0.00

AC:

AN:

1972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Tumoral calcinosis, hyperphosphatemic, familial, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.095

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.29

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.81

REVEL

Benign

0.050

Sift

Pathogenic

0.0

Sift4G

Benign

0.20

Polyphen

0.0

Vest4

0.14

MutPred

0.22

Gain of phosphorylation at P2 (P = 0.0031)

MVP

0.31

MPC

0.95

ClinPred

0.15

GERP RS

-0.29

PromoterAI

0.17

Neutral

(source)

Varity_R

0.080

gMVP

0.36

Mutation Taster

=83/17

polymorphism

(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