rs17025867

Positions:

• chr2-40351419-G-A
• chr2-40351419-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000332839.9(SLC8A1):​c.1808+77054C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 151,744 control chromosomes in the GnomAD database, including 24 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 0.014 (24 hom., cov: 31)
• Consequence: SLC8A1 ENST00000332839.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.014 (2120/151744) while in subpopulation SAS AF= 0.0451 (217/4816). AF 95% confidence interval is 0.0401. There are 24 homozygotes in gnomad4. There are 984 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2120 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC8A1	NM_021097.5	c.1808+77054C>T		intron_variant		ENST00000332839.9	NP_066920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC8A1	ENST00000332839.9	c.1808+77054C>T		intron_variant		1	NM_021097.5	ENSP00000332931	P4

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2128 AN: 151628 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.00909

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00801

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0459

Gnomad FIN AF: 0.00548

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0139

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

GnomAD4 genome AF: 0.0140 AC: 2120 AN: 151744 Hom.: 24 Cov.: 31 AF XY: 0.0133 AC XY: 984 AN XY: 74188

Gnomad4 AFR AF: 0.00907

Gnomad4 AMR AF: 0.00800

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0451

Gnomad4 FIN AF: 0.00548

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00602 Hom.: 2

Bravo AF: 0.0129

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.69
DANN	Benign	0.38

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: rs17025867; hg19: chr2-40578559;