rs2249358

Variant names:

• chr13-33049027-G-A
• rs2249358
• NM_004795.4:c.820-4740G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-33049027-G-A
• chr13-33049027-G-C
• chr13-33049027-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004795.4(KL):​c.820-4740G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 151,964 control chromosomes in the GnomAD database, including 34,130 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.67 (34130 hom., cov: 32)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• Publications: 8 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: AR, Unknown Classification: LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.820-4740G>A		intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.-102-4740G>A		intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1	c.820-4740G>A		intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1	c.820-4740G>A		intron_variant	Intron 1 of 3		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.820-4740G>A		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.828-4740G>A		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.665 AC: 101043 AN: 151846 Hom.: 34090 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.704

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.694

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.666 AC: 101134 AN: 151964 Hom.: 34130 Cov.: 32 AF XY: 0.667 AC XY: 49565 AN XY: 74282

African (AFR) AF: 0.552 AC: 22843 AN: 41394

American (AMR) AF: 0.763 AC: 11667 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2402 AN: 3470

East Asian (EAS) AF: 0.704 AC: 3640 AN: 5168

South Asian (SAS) AF: 0.658 AC: 3167 AN: 4812

European-Finnish (FIN) AF: 0.706 AC: 7446 AN: 10548

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47588 AN: 67974

Other (OTH) AF: 0.695 AC: 1464 AN: 2106

Alfa AF: 0.698 Hom.: 46200

Bravo AF: 0.670

Asia WGS AF: 0.691 AC: 2404 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.74
DANN	Benign	0.80
PhyloP100		-1.4
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: rs2249358; hg19: chr13-33623164;