2-40115460-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_021097.5(SLC8A1):c.2715C>A(p.Gly905=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00918 in 1,614,176 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (82 hom.)
• Consequence: SLC8A1 NM_021097.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.84

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-40115460-G-T is Benign according to our data. Variant chr2-40115460-G-T is described in ClinVar as [Benign]. Clinvar id is 781601.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 1115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC8A1	NM_021097.5	c.2715C>A	p.Gly905=	synonymous_variant	11/11	ENST00000332839.9
SLC8A1-AS1	NR_038441.1	n.121+10498G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC8A1	ENST00000332839.9	c.2715C>A	p.Gly905=	synonymous_variant	11/11	1	NM_021097.5	P4
SLC8A1-AS1	ENST00000599740.1	n.74-136224G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 1115 AN: 152184 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00758 AC: 1907 AN: 251420 Hom.: 7 AF XY: 0.00771 AC XY: 1048 AN XY: 135878

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.00854

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00444

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.00938 AC: 13709 AN: 1461874 Hom.: 82 Cov.: 31 AF XY: 0.00917 AC XY: 6669 AN XY: 727236

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00418

Gnomad4 ASJ exome AF: 0.00792

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00466

Gnomad4 FIN exome AF: 0.0149

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00773

GnomAD4 genome AF: 0.00731 AC: 1113 AN: 152302 Hom.: 11 Cov.: 32 AF XY: 0.00726 AC XY: 541 AN XY: 74474

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00395

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00915 Hom.: 2

Bravo AF: 0.00617

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00976

EpiControl AF: 0.00776

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	10
Dann	Benign	0.89

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: rs148215685; hg19: chr2-40342600; COSMIC: COSV100245295;