20-19281071-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020689.4(SLC24A3):c.255G>C(p.Lys85Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SLC24A3 NM_020689.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

Genes affected

SLC24A3 (HGNC:10977): (solute carrier family 24 member 3) Plasma membrane sodium/calcium exchangers are an important component of intracellular calcium homeostasis and electrical conduction. Potassium-dependent sodium/calcium exchangers such as SLC24A3 are believed to transport 1 intracellular calcium and 1 potassium ion in exchange for 4 extracellular sodium ions (Kraev et al., 2001 [PubMed 11294880]).[supplied by OMIM, Mar 2008]

SLC24A3-AS1 (HGNC:40540): (SLC24A3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14258182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC24A3	NM_020689.4	c.255G>C	p.Lys85Asn	missense_variant	2/17	ENST00000328041.11
SLC24A3-AS1	NR_024564.1	n.529+2068C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC24A3	ENST00000328041.11	c.255G>C	p.Lys85Asn	missense_variant	2/17	1	NM_020689.4	P1
SLC24A3-AS1	ENST00000319682.2	n.529+2068C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251314 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000680

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.255G>C (p.K85N) alteration is located in exon 2 (coding exon 2) of the SLC24A3 gene. This alteration results from a G to C substitution at nucleotide position 255, causing the lysine (K) at amino acid position 85 to be replaced by an asparagine (N). 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	0.53
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.045
Sift	Benign	0.075	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.0070	B;B
Vest4		0.45
MutPred		0.37		Loss of ubiquitination at K85 (P = 0.0039);Loss of ubiquitination at K85 (P = 0.0039);
MVP		0.44
MPC		1.3
ClinPred		0.16	T
GERP RS		3.2
Varity_R		0.094
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs779492472; hg19: chr20-19261715;