rs2003149

Variant names:

• chr18-63355558-C-T
• rs2003149
• NM_002035.4:c.261G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002035.4(KDSR):​c.261G>A​(p.Val87Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 1,583,240 control chromosomes in the GnomAD database, including 330,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28005 hom., cov: 32)
  • Exomes 𝑓: 0.65 (302181 hom.)
• Consequence: KDSR NM_002035.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.468
• Publications: 24 publications found

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]

KDSR Gene-Disease associations (from GenCC):

• erythrokeratodermia variabilis et progressiva 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P
• erythrokeratodermia variabilis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 18-63355558-C-T is Benign according to our data. Variant chr18-63355558-C-T is described in ClinVar as Benign. ClinVar VariationId is 1300062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.468 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDSR	NM_002035.4	c.261G>A	p.Val87Val	synonymous_variant	Exon 4 of 10	ENST00000645214.2	NP_002026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDSR	ENST00000645214.2	c.261G>A	p.Val87Val	synonymous_variant	Exon 4 of 10		NM_002035.4	ENSP00000494352.1

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91428 AN: 151900 Hom.: 27998 Cov.: 32

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.614

GnomAD2 exomes AF: 0.626 AC: 138800 AN: 221614 AF XY: 0.633

Gnomad AFR exome AF: 0.482

Gnomad AMR exome AF: 0.621

Gnomad ASJ exome AF: 0.626

Gnomad EAS exome AF: 0.457

Gnomad FIN exome AF: 0.660

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.636

GnomAD4 exome AF: 0.648 AC: 928138 AN: 1431222 Hom.: 302181 Cov.: 51 AF XY: 0.650 AC XY: 462160 AN XY: 711350

African (AFR) AF: 0.488 AC: 15333 AN: 31450

American (AMR) AF: 0.623 AC: 21720 AN: 34888

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 14883 AN: 24382

East Asian (EAS) AF: 0.482 AC: 19003 AN: 39386

South Asian (SAS) AF: 0.675 AC: 54306 AN: 80428

European-Finnish (FIN) AF: 0.661 AC: 34869 AN: 52788

Middle Eastern (MID) AF: 0.607 AC: 3408 AN: 5612

European-Non Finnish (NFE) AF: 0.659 AC: 727439 AN: 1103274

Other (OTH) AF: 0.630 AC: 37177 AN: 59014

GnomAD4 genome AF: 0.602 AC: 91453 AN: 152018 Hom.: 28005 Cov.: 32 AF XY: 0.600 AC XY: 44563 AN XY: 74286

African (AFR) AF: 0.487 AC: 20174 AN: 41428

American (AMR) AF: 0.628 AC: 9586 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2085 AN: 3470

East Asian (EAS) AF: 0.467 AC: 2413 AN: 5168

South Asian (SAS) AF: 0.659 AC: 3179 AN: 4826

European-Finnish (FIN) AF: 0.644 AC: 6800 AN: 10552

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45139 AN: 67986

Other (OTH) AF: 0.609 AC: 1287 AN: 2112

Alfa AF: 0.640 Hom.: 85074

Bravo AF: 0.588

Asia WGS AF: 0.544 AC: 1892 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Erythrokeratodermia variabilis et progressiva 4 Benign:1

Aug 19, 2021

Genome-Nilou Lab

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	-0.27
CADD	Benign	7.6
DANN	Benign	0.71
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs2003149; hg19: chr18-61022791; COSMIC: COSV58506508; COSMIC: COSV58506508;