2-40177826-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000406391.2(SLC8A1):c.1838G>A(p.Arg613His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00532 in 1,550,724 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (22 hom.)
• Consequence: SLC8A1 ENST00000406391.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.828

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00810191).
• BP6: Variant 2-40177826-C-T is Benign according to our data. Variant chr2-40177826-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2650849.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-40177826-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 695 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC8A1	NM_021097.5	c.1915+561G>A		intron_variant		ENST00000332839.9
SLC8A1-AS1	NR_038441.1	n.121+72864C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC8A1	ENST00000332839.9	c.1915+561G>A		intron_variant		1	NM_021097.5	P4
SLC8A1-AS1	ENST00000599740.1	n.74-73858C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 695 AN: 152112 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00628

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00375 AC: 587 AN: 156610 Hom.: 1 AF XY: 0.00370 AC XY: 307 AN XY: 82944

Gnomad AFR exome AF: 0.00239

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00212

Gnomad EAS exome AF: 0.0000903

Gnomad SAS exome AF: 0.00224

Gnomad FIN exome AF: 0.00362

Gnomad NFE exome AF: 0.00574

Gnomad OTH exome AF: 0.00776

GnomAD4 exome AF: 0.00541 AC: 7559 AN: 1398494 Hom.: 22 Cov.: 30 AF XY: 0.00533 AC XY: 3678 AN XY: 689806

Gnomad4 AFR exome AF: 0.00339

Gnomad4 AMR exome AF: 0.00317

Gnomad4 ASJ exome AF: 0.00278

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00241

Gnomad4 FIN exome AF: 0.00331

Gnomad4 NFE exome AF: 0.00616

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.00457 AC: 696 AN: 152230 Hom.: 2 Cov.: 33 AF XY: 0.00402 AC XY: 299 AN XY: 74426

Gnomad4 AFR AF: 0.00347

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00628

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00497 Hom.: 3

Bravo AF: 0.00482

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00506 AC: 7

ESP6500EA AF: 0.00660 AC: 21

ExAC AF: 0.00347 AC: 90

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

SLC8A1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.0081	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;N;N;N;N;N;N
PROVEAN	Benign	0.70	N;N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.052	T;T;T;T;T
Sift4G	Uncertain	0.034	D;D;D;D;D
Polyphen		0.31	B;B;B;P;B
Vest4		0.19
MVP		0.38
ClinPred		0.019	T
GERP RS		3.5

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: rs5556; hg19: chr2-40404966; COSMIC: COSV104654781;