4-39446922-C-G

Variant names:

• chr4-39446922-C-G
• rs7685429
• NM_175737.4:c.2196C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_175737.4(KLB):​c.2196C>G​(p.Pro732Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 1,604,292 control chromosomes in the GnomAD database, including 464,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43310 hom., cov: 35)
  • Exomes 𝑓: 0.76 (421583 hom.)
• Consequence: KLB NM_175737.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.24
• Publications: 19 publications found

Genes affected

KLB (HGNC:15527): (klotho beta) Enables fibroblast growth factor binding activity and fibroblast growth factor receptor binding activity. Predicted to be involved in fibroblast growth factor receptor signaling pathway. Predicted to act upstream of or within positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway and positive regulation of cell population proliferation. Predicted to be located in plasma membrane. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-39446922-C-G is Benign according to our data. Variant chr4-39446922-C-G is described in ClinVar as Benign. ClinVar VariationId is 1542991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLB	NM_175737.4	c.2196C>G	p.Pro732Pro	synonymous_variant	Exon 4 of 5	ENST00000257408.5	NP_783864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLB	ENST00000257408.5	c.2196C>G	p.Pro732Pro	synonymous_variant	Exon 4 of 5	1	NM_175737.4	ENSP00000257408.4

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114506 AN: 152136 Hom.: 43272 Cov.: 35

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.883

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.699

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.766

Gnomad OTH AF: 0.764

GnomAD2 exomes AF: 0.768 AC: 182514 AN: 237584 AF XY: 0.767

Gnomad AFR exome AF: 0.719

Gnomad AMR exome AF: 0.827

Gnomad ASJ exome AF: 0.742

Gnomad EAS exome AF: 0.734

Gnomad FIN exome AF: 0.706

Gnomad NFE exome AF: 0.766

Gnomad OTH exome AF: 0.773

GnomAD4 exome AF: 0.761 AC: 1105605 AN: 1452038 Hom.: 421583 Cov.: 77 AF XY: 0.762 AC XY: 550377 AN XY: 722588

African (AFR) AF: 0.717 AC: 23984 AN: 33444

American (AMR) AF: 0.827 AC: 36814 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 19351 AN: 25918

East Asian (EAS) AF: 0.730 AC: 28942 AN: 39668

South Asian (SAS) AF: 0.785 AC: 67464 AN: 85946

European-Finnish (FIN) AF: 0.707 AC: 32451 AN: 45898

Middle Eastern (MID) AF: 0.716 AC: 4119 AN: 5752

European-Non Finnish (NFE) AF: 0.763 AC: 847071 AN: 1110660

Other (OTH) AF: 0.754 AC: 45409 AN: 60246

GnomAD4 genome AF: 0.753 AC: 114606 AN: 152254 Hom.: 43310 Cov.: 35 AF XY: 0.749 AC XY: 55801 AN XY: 74454

African (AFR) AF: 0.718 AC: 29832 AN: 41556

American (AMR) AF: 0.810 AC: 12385 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2639 AN: 3472

East Asian (EAS) AF: 0.738 AC: 3822 AN: 5178

South Asian (SAS) AF: 0.786 AC: 3796 AN: 4828

European-Finnish (FIN) AF: 0.699 AC: 7413 AN: 10604

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

European-Non Finnish (NFE) AF: 0.766 AC: 52073 AN: 67996

Other (OTH) AF: 0.767 AC: 1624 AN: 2116

Alfa AF: 0.712 Hom.: 5219

Bravo AF: 0.761

Asia WGS AF: 0.790 AC: 2751 AN: 3478

EpiCase AF: 0.770

EpiControl AF: 0.776

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.86
CADD	Benign	0.20
DANN	Benign	0.72
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7685429; hg19: chr4-39448542; COSMIC: COSV57300797;