dbSNP rs2283368: KL:c.819+1873T>C (chr13-33019132-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004795.4(KL):c.819+1873T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 152,148 control chromosomes in the GnomAD database, including 1,835 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.15 ( 1835 hom., cov: 32)

Consequence

KL
NM_004795.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.143

Publications

21 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4 link	c.819+1873T>C	intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2	Q9UEF7-1
KL	XM_006719895.3 link	c.-103+2819T>C	intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1 link	c.819+1873T>C	intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1 link	c.819+1873T>C	intron_variant	Intron 1 of 3		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4 link	c.819+1873T>C		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3		Q9UEF7-1
KL	ENST00000487852.1 link	n.827+1873T>C		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22385

AN:

152030

Hom.:

1833

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.0920

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.204

Gnomad SAS

AF:

0.248

Gnomad FIN

AF:

0.197

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.123

Gnomad OTH

AF:

0.136

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.147

AC:

22402

AN:

152148

Hom.:

1835

Cov.:

AF XY:

0.152

AC XY:

11302

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.178

AC:

7376

AN:

41522

American (AMR)

AF:

0.0918

AC:

1404

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

467

AN:

3472

East Asian (EAS)

AF:

0.204

AC:

1056

AN:

5188

South Asian (SAS)

AF:

0.248

AC:

1194

AN:

4808

European-Finnish (FIN)

AF:

0.197

AC:

2086

AN:

10574

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.123

AC:

8393

AN:

67978

Other (OTH)

AF:

0.134

AC:

283

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

968

1936

2903

3871

4839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.132

Hom.:

1417

Bravo

AF:

0.139

Asia WGS

AF:

0.188

AC:

652

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.7

(source)

DANN

Benign

0.81

PhyloP100

-0.14

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over