2-40115284-A-G

Variant names:

• chr2-40115284-A-G
• NM_021097.5:c.2891T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021097.5(SLC8A1):​c.2891T>C​(p.Leu964Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC8A1 NM_021097.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.20
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021097.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC8A1	NM_021097.5	MANE Select	c.2891T>C	p.Leu964Pro	missense	Exon 11 of 11	NP_066920.1	P32418-1
	SLC8A1	NM_001372263.2		c.2891T>C	p.Leu964Pro	missense	Exon 11 of 11	NP_001359192.1	P32418-1
	SLC8A1	NM_001394103.1		c.2891T>C	p.Leu964Pro	missense	Exon 12 of 12	NP_001381032.1	P32418-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC8A1	ENST00000332839.9	TSL:1 MANE Select	c.2891T>C	p.Leu964Pro	missense	Exon 11 of 11	ENSP00000332931.4	P32418-1
	SLC8A1	ENST00000403092.5	TSL:1	c.2891T>C	p.Leu964Pro	missense	Exon 11 of 11	ENSP00000384763.1	P32418-1
	SLC8A1	ENST00000405901.7	TSL:1	c.2876T>C	p.Leu959Pro	missense	Exon 9 of 9	ENSP00000385678.3	P32418-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.69		Loss of helix (P = 0.0104)
MVP		0.92
MPC		2.6
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.92
gMVP		0.99
Mutation Taster		=0/100	disease causing

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

Other links and lift over

hg19: chr2-40342424;