20-19673632-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_020689.4(SLC24A3):c.745C>G(p.Leu249Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,613,782 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (34 hom.)
• Consequence: SLC24A3 NM_020689.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.427

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059251487).
• BP6: Variant 20-19673632-C-G is Benign according to our data. Variant chr20-19673632-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3234185.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC24A3	NM_020689.4	c.745C>G	p.Leu249Val	missense_variant	9/17	ENST00000328041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC24A3	ENST00000328041.11	c.745C>G	p.Leu249Val	missense_variant	9/17	1	NM_020689.4	P1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152200 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00273 AC: 686 AN: 251384 Hom.: 4 AF XY: 0.00262 AC XY: 356 AN XY: 135866

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00453 AC: 6615 AN: 1461464 Hom.: 34 Cov.: 30 AF XY: 0.00433 AC XY: 3150 AN XY: 727058

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00554

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.00270 AC: 412 AN: 152318 Hom.: 2 Cov.: 33 AF XY: 0.00262 AC XY: 195 AN XY: 74478

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00510

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00471 Hom.: 2

Bravo AF: 0.00255

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00299 AC: 363

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00545

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

SLC24A3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	11
Dann	Benign	0.55
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.031	N
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.29	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.26	N;.
REVEL	Benign	0.12
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.27
MVP		0.35
MPC		0.50
ClinPred		0.0023	T
GERP RS		-3.3
Varity_R		0.091
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs148897045; hg19: chr20-19654276;