chr18-63331816-C-G

Variant names:

• chr18-63331816-C-G
• rs771254281
• NM_002035.4:c.965G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002035.4(KDSR):​c.965G>C​(p.Arg322Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDSR NM_002035.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80
• Publications: 0 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, G2P, Genomics England PanelApp
• erythrokeratodermia variabilis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35385185).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002035.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDSR	NM_002035.4	MANE Select	c.965G>C	p.Arg322Thr	missense	Exon 10 of 10	NP_002026.1	Q06136-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDSR	ENST00000645214.2	MANE Select	c.965G>C	p.Arg322Thr	missense	Exon 10 of 10	ENSP00000494352.1	Q06136-1
	KDSR	ENST00000951441.1		c.1055G>C	p.Arg352Thr	missense	Exon 11 of 11	ENSP00000621500.1
	KDSR	ENST00000882920.1		c.971G>C	p.Arg324Thr	missense	Exon 10 of 10	ENSP00000552979.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.8
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.79	P
Vest4		0.37
MutPred		0.42		Gain of glycosylation at R322 (P = 0.0515)
MVP		0.96
MPC		0.54
ClinPred		0.97	D
GERP RS		2.1
Varity_R		0.27
gMVP		0.87
Mutation Taster		=82/18	polymorphism

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: rs771254281; hg19: chr18-60999049;