rs2149860

Variant names:

• chr13-33054852-A-G
• rs2149860
• NM_004795.4:c.1331-195A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004795.4(KL):​c.1331-195A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 152,020 control chromosomes in the GnomAD database, including 14,574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.43 (14574 hom., cov: 32)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.254
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 13-33054852-A-G is Benign according to our data. Variant chr13-33054852-A-G is described in CliVar as Benign. Clinvar id is 1234670.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-33054852-A-G is described in CliVar as Benign. Clinvar id is 1234670.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.1331-195A>G		intron_variant	Intron 2 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.410-195A>G		intron_variant	Intron 2 of 4		XP_006719958.1
KL	XM_047430775.1	c.1331-195A>G		intron_variant	Intron 2 of 3		XP_047286731.1
KL	XM_047430776.1	c.1331-195A>G		intron_variant	Intron 2 of 3		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.1331-195A>G		intron_variant	Intron 2 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.1339-195A>G		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65858 AN: 151902 Hom.: 14567 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.444

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

GnomAD4 genome AF: 0.433 AC: 65890 AN: 152020 Hom.: 14574 Cov.: 32 AF XY: 0.436 AC XY: 32384 AN XY: 74286

African (AFR) AF: 0.424 AC: 17565 AN: 41464

American (AMR) AF: 0.321 AC: 4900 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1677 AN: 3470

East Asian (EAS) AF: 0.452 AC: 2333 AN: 5166

South Asian (SAS) AF: 0.493 AC: 2371 AN: 4814

European-Finnish (FIN) AF: 0.498 AC: 5251 AN: 10552

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30316 AN: 67978

Other (OTH) AF: 0.439 AC: 926 AN: 2108

Alfa AF: 0.429 Hom.: 4063

Bravo AF: 0.418

Asia WGS AF: 0.425 AC: 1477 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.0
DANN	Benign	0.35
PhyloP100		0.25
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: rs2149860; hg19: chr13-33628989;