13-33061326-T-C

Variant names:

• chr13-33061326-T-C
• rs648202
• NM_004795.4:c.2247T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 33 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 311701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.2247T>C	p.Ala749Ala	synonymous	Exon 4 of 5	NP_004786.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	ENST00000380099.4	TSL:1 MANE Select	c.2247T>C	p.Ala749Ala	synonymous	Exon 4 of 5	ENSP00000369442.3	Q9UEF7-1
	KL	ENST00000487852.1	TSL:5	n.2305T>C		non_coding_transcript_exon	Exon 4 of 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

GnomAD2 exomes AF: 0.808 AC: 203112 AN: 251232 AF XY: 0.816

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 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

African (AFR) AF: 0.572 AC: 19137 AN: 33478

American (AMR) AF: 0.795 AC: 35574 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 23771 AN: 26136

East Asian (EAS) AF: 0.627 AC: 24887 AN: 39700

South Asian (SAS) AF: 0.814 AC: 70188 AN: 86258

European-Finnish (FIN) AF: 0.881 AC: 47078 AN: 53414

Middle Eastern (MID) AF: 0.839 AC: 4837 AN: 5768

European-Non Finnish (NFE) AF: 0.856 AC: 951802 AN: 1111996

Other (OTH) AF: 0.823 AC: 49717 AN: 60394

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

African (AFR) AF: 0.579 AC: 23974 AN: 41416

American (AMR) AF: 0.798 AC: 12190 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 3165 AN: 3468

East Asian (EAS) AF: 0.616 AC: 3182 AN: 5168

South Asian (SAS) AF: 0.802 AC: 3868 AN: 4824

European-Finnish (FIN) AF: 0.884 AC: 9373 AN: 10598

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.855 AC: 58163 AN: 68016

Other (OTH) AF: 0.813 AC: 1716 AN: 2110

Alfa AF: 0.831 Hom.: 107881

Bravo AF: 0.755

Asia WGS AF: 0.700 AC: 2439 AN: 3478

EpiCase AF: 0.862

EpiControl AF: 0.860

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Tumoral calcinosis, hyperphosphatemic, familial, 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.41
PhyloP100		-4.2
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs648202; hg19: chr13-33635463; COSMIC: COSV108226555;