rs2238166

Variant names:

• chr13-33020543-C-T
• rs2238166
• NM_004795.4:c.819+3284C>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.819+3284C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 151,828 control chromosomes in the GnomAD database, including 8,357 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 0.31 (8357 hom., cov: 31)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.65
• Publications: 1 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.819+3284C>T		intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.-103+4230C>T		intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1	c.819+3284C>T		intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1	c.819+3284C>T		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.819+3284C>T		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.827+3284C>T		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.310 AC: 46980 AN: 151710 Hom.: 8347 Cov.: 31

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.336

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

GnomAD4 genome AF: 0.310 AC: 47003 AN: 151828 Hom.: 8357 Cov.: 31 AF XY: 0.308 AC XY: 22873 AN XY: 74194

African (AFR) AF: 0.148 AC: 6146 AN: 41488

American (AMR) AF: 0.434 AC: 6617 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1268 AN: 3468

East Asian (EAS) AF: 0.161 AC: 835 AN: 5180

South Asian (SAS) AF: 0.241 AC: 1161 AN: 4808

European-Finnish (FIN) AF: 0.359 AC: 3786 AN: 10532

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26020 AN: 67820

Other (OTH) AF: 0.339 AC: 710 AN: 2094

Alfa AF: 0.330 Hom.: 1183

Bravo AF: 0.313

Asia WGS AF: 0.255 AC: 887 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.029
DANN	Benign	0.74
PhyloP100		-2.7
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: rs2238166; hg19: chr13-33594681;