chr15-48134956-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_205850.3(SLC24A5):ā€‹c.562G>Cā€‹(p.Gly188Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

SLC24A5
NM_205850.3 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.27
Variant links:
Genes affected
SLC24A5 (HGNC:20611): (solute carrier family 24 member 5) This gene is a member of the potassium-dependent sodium/calcium exchanger family and encodes an intracellular membrane protein with 2 large hydrophilic loops and 2 sets of multiple transmembrane-spanning segments. Sequence variation in this gene has been associated with differences in skin pigmentation. [provided by RefSeq, Jul 2008]
MYEF2 (HGNC:17940): (myelin expression factor 2) Enables RNA binding activity. Involved in myotube differentiation and neuron differentiation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a transmembrane_region Helical; Name=4 (size 20) in uniprot entity NCKX5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_205850.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC24A5NM_205850.3 linkuse as main transcriptc.562G>C p.Gly188Arg missense_variant 5/9 ENST00000341459.8
MYEF2NM_016132.5 linkuse as main transcriptc.*7952C>G 3_prime_UTR_variant 17/17 ENST00000324324.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC24A5ENST00000341459.8 linkuse as main transcriptc.562G>C p.Gly188Arg missense_variant 5/91 NM_205850.3 P1Q71RS6-1
SLC24A5ENST00000449382.2 linkuse as main transcriptc.382G>C p.Gly128Arg missense_variant 4/81 Q71RS6-2
MYEF2ENST00000324324.12 linkuse as main transcriptc.*7952C>G 3_prime_UTR_variant 17/171 NM_016132.5 P4
SLC24A5ENST00000463289.1 linkuse as main transcriptn.322G>C non_coding_transcript_exon_variant 4/53

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250678
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135482
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459450
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
725816
show subpopulations
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 20, 2023The c.562G>C (p.G188R) alteration is located in exon 5 (coding exon 5) of the SLC24A5 gene. This alteration results from a G to C substitution at nucleotide position 562, causing the glycine (G) at amino acid position 188 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Uncertain
0.018
T
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.46
T;.
Eigen
Uncertain
0.66
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.053
D
MetaRNN
Pathogenic
0.85
D;D
MetaSVM
Benign
-0.60
T
MutationAssessor
Benign
1.1
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.6
N;N
REVEL
Benign
0.24
Sift
Uncertain
0.025
D;D
Sift4G
Uncertain
0.041
D;T
Polyphen
0.78
P;.
Vest4
0.60
MutPred
0.85
Gain of methylation at G188 (P = 0.0295);.;
MVP
0.81
MPC
0.094
ClinPred
0.58
D
GERP RS
5.6
Varity_R
0.55
gMVP
0.84

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: rs1335131907; hg19: chr15-48427153; API