rs1555407654

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000261892.11(SLC24A1):​c.2968A>C​(p.Ser990Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SLC24A1
ENST00000261892.11 missense

Scores

15
3
1

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 9.28
Variant links:
Genes affected
SLC24A1 (HGNC:10975): (solute carrier family 24 member 1) This gene encodes a member of the potassium-dependent sodium/calcium exchanger protein family. The encoded protein plays an important role in sodium/calcium exchange in retinal rod and cone photoreceptors by mediating the extrusion of one calcium ion and one potassium ion in exchange for four sodium ions. Mutations in this gene may play a role in congenital stationary night blindness. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC24A1NM_004727.3 linkuse as main transcriptc.2968A>C p.Ser990Arg missense_variant 9/10 ENST00000261892.11 NP_004718.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC24A1ENST00000261892.11 linkuse as main transcriptc.2968A>C p.Ser990Arg missense_variant 9/101 NM_004727.3 ENSP00000261892 P4O60721-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital stationary night blindness 1D Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 13, 2018- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 17, 2020In 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with congenital stationary night blindess (PMID: 26822852). ClinVar contains an entry for this variant (Variation ID: 489400). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 990 of the SLC24A1 protein (p.Ser990Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T;D;.;.;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;D;D;.;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Pathogenic
5.1
.;H;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-4.6
D;D;.;D;D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D;.;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
D;D;.;.;.;D
Vest4
0.98
MutPred
0.88
.;Loss of catalytic residue at D986 (P = 0.1475);.;.;.;.;
MVP
0.98
MPC
0.87
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.94
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555407654; hg19: chr15-65945064; API