13-33061698-T-C

Position:

• chr13-33061698-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.2619T>C​(p.Asn873=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,613,994 control chromosomes in the GnomAD database, including 799,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72414 hom., cov: 31)
  • Exomes 𝑓: 1.0 (727192 hom.)
• Consequence: KL NM_004795.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.231

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-33061698-T-C is Benign according to our data. Variant chr13-33061698-T-C is described in ClinVar as [Benign]. Clinvar id is 311705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-33061698-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.231 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) 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.2619T>C	p.Asn873=	synonymous_variant	4/5	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.1698T>C	p.Asn566=	synonymous_variant	4/5		XP_006719958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.2619T>C	p.Asn873=	synonymous_variant	4/5	1	NM_004795.4	ENSP00000369442	P1
KL	ENST00000487852.1	n.2677T>C		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.974 AC: 148257 AN: 152138 Hom.: 72357 Cov.: 31

Gnomad AFR AF: 0.912

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.988

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.983

GnomAD3 exomes AF: 0.994 AC: 249797 AN: 251402 Hom.: 124150 AF XY: 0.995 AC XY: 135242 AN XY: 135876

Gnomad AFR exome AF: 0.914

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 1.00

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: 0.997

GnomAD4 exome AF: 0.997 AC: 1457932 AN: 1461738 Hom.: 727192 Cov.: 55 AF XY: 0.998 AC XY: 725542 AN XY: 727148

Gnomad4 AFR exome AF: 0.912

Gnomad4 AMR exome AF: 0.994

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.994

GnomAD4 genome AF: 0.974 AC: 148373 AN: 152256 Hom.: 72414 Cov.: 31 AF XY: 0.976 AC XY: 72647 AN XY: 74450

Gnomad4 AFR AF: 0.912

Gnomad4 AMR AF: 0.988

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.983

Alfa AF: 0.993 Hom.: 77656

Bravo AF: 0.970

Asia WGS AF: 0.995 AC: 3461 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

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	GeneDx	May 04, 2021	- -
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	-	- -

Tumoral calcinosis, hyperphosphatemic, familial, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.061
DANN	Benign	0.29

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: rs649964; hg19: chr13-33635835;