chr13-33061698-T-C

Variant names:

• chr13-33061698-T-C
• rs649964
• NM_004795.4:c.2619T>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.2619T>C​(p.Asn873Asn) 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
• Publications: 19 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=-0.82).
• BP6: Variant 13-33061698-T-C is Benign according to our data. Variant chr13-33061698-T-C is described in ClinVar as Benign. ClinVar VariationId is 311705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.2619T>C	p.Asn873Asn	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.2619T>C	p.Asn873Asn	synonymous	Exon 4 of 5	ENSP00000369442.3	Q9UEF7-1
	KL	ENST00000487852.1	TSL:5	n.2677T>C		non_coding_transcript_exon	Exon 4 of 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

GnomAD2 exomes AF: 0.994 AC: 249797 AN: 251402 AF XY: 0.995

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 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

African (AFR) AF: 0.912 AC: 30514 AN: 33476

American (AMR) AF: 0.994 AC: 44472 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26133 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39694 AN: 39694

South Asian (SAS) AF: 1.00 AC: 86236 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 53416 AN: 53416

Middle Eastern (MID) AF: 0.996 AC: 5745 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111679 AN: 1111874

Other (OTH) AF: 0.994 AC: 60043 AN: 60394

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

African (AFR) AF: 0.912 AC: 37880 AN: 41514

American (AMR) AF: 0.988 AC: 15114 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5176 AN: 5178

South Asian (SAS) AF: 1.00 AC: 4819 AN: 4820

European-Finnish (FIN) AF: 1.00 AC: 10616 AN: 10616

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68013 AN: 68032

Other (OTH) AF: 0.983 AC: 2079 AN: 2114

Alfa AF: 0.990 Hom.: 99497

Bravo AF: 0.970

Asia WGS AF: 0.995 AC: 3461 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

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	-0.82
CADD	Benign	0.061
DANN	Benign	0.29
PhyloP100		-0.23
Mutation Taster		=100/0	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: rs649964; hg19: chr13-33635835; COSMIC: COSV108226656;