2-40605492-G-A

Position:

• chr2-40605492-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000405269.5(SLC8A1):​c.-25+5438C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 151,980 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.045 (224 hom., cov: 32)
• Consequence: SLC8A1 ENST00000405269.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.40605492G>A		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC8A1	ENST00000405269.5	c.-25+5438C>T		intron_variant		5		ENSP00000385535.1
ENSG00000285898	ENST00000649978.1	n.448+10852G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6819 AN: 151862 Hom.: 224 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0469

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0621

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0653

Gnomad OTH AF: 0.0446

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0448 AC: 6815 AN: 151980 Hom.: 224 Cov.: 32 AF XY: 0.0430 AC XY: 3197 AN XY: 74284

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.0469

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0619

Gnomad4 FIN AF: 0.0250

Gnomad4 NFE AF: 0.0653

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0656 Hom.: 464

Bravo AF: 0.0441

Asia WGS AF: 0.0250 AC: 86 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.24

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10195113; hg19: chr2-40832632;