18-63367055-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002035.4(KDSR):c.64C>G(p.Leu22Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000849 in 1,178,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: KDSR NM_002035.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.07

Genes affected

KDSR (HGNC:4021): (3-ketodihydrosphingosine reductase) The protein encoded by this gene catalyzes the reduction of 3-ketodihydrosphingosine to dihydrosphingosine. The putative active site residues of the encoded protein are found on the cytosolic side of the endoplasmic reticulum membrane. A chromosomal rearrangement involving this gene is a cause of follicular lymphoma, also known as type II chronic lymphatic leukemia. The mutation of a conserved residue in the bovine ortholog causes spinal muscular atrophy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDSR	NM_002035.4	c.64C>G	p.Leu22Val	missense_variant	1/10	ENST00000645214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDSR	ENST00000645214.2	c.64C>G	p.Leu22Val	missense_variant	1/10		NM_002035.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.49e-7 AC: 1 AN: 1178178 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 568316

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000104

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with KDSR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 22 of the KDSR protein (p.Leu22Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Benign	0.29	T;T;.;.;T
Eigen	Benign	-0.019
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Uncertain	0.018	D
MutationAssessor	Benign	0.69	N;N;.;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
Polyphen		0.0040	B;B;.;.;.
Vest4		0.37, 0.48
MutPred		0.40		Loss of ubiquitination at K26 (P = 0.0795);Loss of ubiquitination at K26 (P = 0.0795);Loss of ubiquitination at K26 (P = 0.0795);Loss of ubiquitination at K26 (P = 0.0795);Loss of ubiquitination at K26 (P = 0.0795);
MVP		0.95
MPC		0.29
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.45
gMVP		0.49

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-61034288;