13-33061326-T-C

Position:

• chr13-33061326-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.2247T>C​(p.Ala749Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,613,948 control chromosomes in the GnomAD database, including 563,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (46020 hom., cov: 31)
  • Exomes 𝑓: 0.84 (517734 hom.)
• Consequence: KL NM_004795.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.21

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=-0.92).
• BP6: Variant 13-33061326-T-C is Benign according to our data. Variant chr13-33061326-T-C is described in ClinVar as [Benign]. Clinvar id is 311701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-33061326-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KL	NM_004795.4	c.2247T>C	p.Ala749Ala	synonymous_variant	4/5	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.1326T>C	p.Ala442Ala	synonymous_variant	4/5		XP_006719958.1
KL	XM_047430776.1	c.*647T>C		3_prime_UTR_variant	4/4		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.2247T>C	p.Ala749Ala	synonymous_variant	4/5	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.2305T>C		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116611 AN: 151962 Hom.: 45991 Cov.: 31

Gnomad AFR AF: 0.579

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.798

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.801

Gnomad FIN AF: 0.884

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.814

GnomAD3 exomes AF: 0.808 AC: 203112 AN: 251232 Hom.: 83319 AF XY: 0.816 AC XY: 110836 AN XY: 135848

Gnomad AFR exome AF: 0.571

Gnomad AMR exome AF: 0.789

Gnomad ASJ exome AF: 0.907

Gnomad EAS exome AF: 0.601

Gnomad SAS exome AF: 0.813

Gnomad FIN exome AF: 0.879

Gnomad NFE exome AF: 0.857

Gnomad OTH exome AF: 0.835

GnomAD4 exome AF: 0.839 AC: 1226991 AN: 1461868 Hom.: 517734 Cov.: 71 AF XY: 0.840 AC XY: 611014 AN XY: 727236

Gnomad4 AFR exome AF: 0.572

Gnomad4 AMR exome AF: 0.795

Gnomad4 ASJ exome AF: 0.910

Gnomad4 EAS exome AF: 0.627

Gnomad4 SAS exome AF: 0.814

Gnomad4 FIN exome AF: 0.881

Gnomad4 NFE exome AF: 0.856

Gnomad4 OTH exome AF: 0.823

GnomAD4 genome AF: 0.767 AC: 116683 AN: 152080 Hom.: 46020 Cov.: 31 AF XY: 0.768 AC XY: 57072 AN XY: 74352

Gnomad4 AFR AF: 0.579

Gnomad4 AMR AF: 0.798

Gnomad4 ASJ AF: 0.913

Gnomad4 EAS AF: 0.616

Gnomad4 SAS AF: 0.802

Gnomad4 FIN AF: 0.884

Gnomad4 NFE AF: 0.855

Gnomad4 OTH AF: 0.813

Alfa AF: 0.837 Hom.: 90405

Bravo AF: 0.755

Asia WGS AF: 0.700 AC: 2439 AN: 3478

EpiCase AF: 0.862

EpiControl AF: 0.860

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Tumoral calcinosis, hyperphosphatemic, familial, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.41

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: rs648202; hg19: chr13-33635463;