rs2772364

Positions:

• chr13-33016713-T-C

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.273T>C​(p.Asp91Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,610,264 control chromosomes in the GnomAD database, including 790,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68934 hom., cov: 31)
  • Exomes 𝑓: 0.99 (722053 hom.)
• Consequence: KL NM_004795.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.04

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 13-33016713-T-C is Benign according to our data. Variant chr13-33016713-T-C is described in ClinVar as [Benign]. Clinvar id is 311680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-33016713-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KL	NM_004795.4	c.273T>C	p.Asp91Asp	synonymous_variant	1/5	ENST00000380099.4	NP_004786.2
KL	XM_047430775.1	c.273T>C	p.Asp91Asp	synonymous_variant	1/4		XP_047286731.1
KL	XM_047430776.1	c.273T>C	p.Asp91Asp	synonymous_variant	1/4		XP_047286732.1
KL	XM_006719895.3	c.-103+400T>C		intron_variant			XP_006719958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.273T>C	p.Asp91Asp	synonymous_variant	1/5	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.281T>C		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.950 AC: 144198 AN: 151858 Hom.: 68894 Cov.: 31

Gnomad AFR AF: 0.825

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.979

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.968

GnomAD3 exomes AF: 0.988 AC: 231274 AN: 234070 Hom.: 114417 AF XY: 0.991 AC XY: 127847 AN XY: 129064

Gnomad AFR exome AF: 0.824

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.993

GnomAD4 exome AF: 0.995 AC: 1450643 AN: 1458290 Hom.: 722053 Cov.: 79 AF XY: 0.995 AC XY: 721940 AN XY: 725268

Gnomad4 AFR exome AF: 0.822

Gnomad4 AMR exome AF: 0.989

Gnomad4 ASJ exome AF: 0.999

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.988

GnomAD4 genome AF: 0.949 AC: 144291 AN: 151974 Hom.: 68934 Cov.: 31 AF XY: 0.951 AC XY: 70651 AN XY: 74304

Gnomad4 AFR AF: 0.825

Gnomad4 AMR AF: 0.979

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.969

Alfa AF: 0.986 Hom.: 23970

Bravo AF: 0.941

Asia WGS AF: 0.989 AC: 3441 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Tumoral calcinosis, hyperphosphatemic, familial, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.77

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: rs2772364; hg19: chr13-33590851; COSMIC: COSV66308010;