2-40520865-T-G

Variant names:

• chr2-40520865-T-G
• rs4952632
• ENST00000405269.5:c.-25+90065A>C

Variant summary

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

The ENST00000405269.5(SLC8A1):​c.-25+90065A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0896 in 152,030 control chromosomes in the GnomAD database, including 1,143 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 0.090 (1143 hom., cov: 32)
• Consequence: SLC8A1 ENST00000405269.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.462

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]

ENSG00000287255 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC101929667	XR_007086295.1	n.166+8778T>G		intron_variant	Intron 1 of 4
LOC101929667	XR_244991.5	n.245+7031T>G		intron_variant	Intron 2 of 5
LOC101929667	XR_427021.5	n.166+8778T>G		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC8A1	ENST00000405269.5	c.-25+90065A>C		intron_variant	Intron 1 of 7	5		ENSP00000385535.1
ENSG00000287255	ENST00000688930.1	n.262+6475T>G		intron_variant	Intron 3 of 6
ENSG00000287255	ENST00000703001.1	n.166+8778T>G		intron_variant	Intron 1 of 4
ENSG00000287255	ENST00000703033.1	n.246+6475T>G		intron_variant	Intron 2 of 5

Frequencies

GnomAD3 genomes AF: 0.0895 AC: 13591 AN: 151912 Hom.: 1140 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0438

Gnomad OTH AF: 0.0986

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

GnomAD4 genome AF: 0.0896 AC: 13618 AN: 152030 Hom.: 1143 Cov.: 32 AF XY: 0.0931 AC XY: 6925 AN XY: 74350

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.426

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0524

Gnomad4 NFE AF: 0.0438

Gnomad4 OTH AF: 0.0980

Alfa AF: 0.0530 Hom.: 416

Bravo AF: 0.104

Asia WGS AF: 0.281 AC: 978 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.93
DANN	Benign	0.48

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4952632; hg19: chr2-40748005;