2-40164928-C-T

Variant names:

• chr2-40164928-C-T
• rs1476572047
• NM_021097.5:c.2095G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021097.5(SLC8A1):​c.2095G>A​(p.Ala699Thr) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC8A1 NM_021097.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75

Genes affected

SLC8A1 (HGNC:11068): (solute carrier family 8 member A1) In cardiac myocytes, Ca(2+) concentrations alternate between high levels during contraction and low levels during relaxation. The increase in Ca(2+) concentration during contraction is primarily due to release of Ca(2+) from intracellular stores. However, some Ca(2+) also enters the cell through the sarcolemma (plasma membrane). During relaxation, Ca(2+) is sequestered within the intracellular stores. To prevent overloading of intracellular stores, the Ca(2+) that entered across the sarcolemma must be extruded from the cell. The Na(+)-Ca(2+) exchanger is the primary mechanism by which the Ca(2+) is extruded from the cell during relaxation. In the heart, the exchanger may play a key role in digitalis action. The exchanger is the dominant mechanism in returning the cardiac myocyte to its resting state following excitation.[supplied by OMIM, Apr 2004]

SLC8A1-AS1 (HGNC:44102): (SLC8A1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC8A1	NM_021097.5	c.2095G>A	p.Ala699Thr	missense_variant	Exon 8 of 11	ENST00000332839.9	NP_066920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC8A1	ENST00000332839.9	c.2095G>A	p.Ala699Thr	missense_variant	Exon 8 of 11	1	NM_021097.5	ENSP00000332931.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2095G>A (p.A699T) alteration is located in exon 7 (coding exon 7) of the SLC8A1 gene. This alteration results from a G to A substitution at nucleotide position 2095, causing the alanine (A) at amino acid position 699 to be replaced by a threonine (T). 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	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	.;D;.;.;.;.;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;.;D;.;.;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.9	.;M;.;.;.;.;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D;D;D;D;D;D;D;D
Sift4G	Benign	0.076	T;T;T;T;T;T;T;T
Polyphen		0.96	D;D;.;D;D;.;D;D
Vest4		0.73
MutPred		0.51		.;Gain of phosphorylation at A699 (P = 0.0108);.;.;.;.;Gain of phosphorylation at A699 (P = 0.0108);.;
MVP		0.47
MPC		0.71
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.26
gMVP		0.58

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: rs1476572047; hg19: chr2-40392068;