rs1570624

chr6-52454252-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_018100.4(EFHC1):c.881G>A(p.Arg294His) variant causes a missense change. The variant allele was found at a frequency of 0.0108 in 1,614,098 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (13 hom., cov: 32)
  • Exomes 𝑓: 0.011 (122 hom.)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.04

Genes affected

EFHC1 (HGNC:16406): (EF-hand domain containing 1) This gene encodes an EF-hand-containing calcium binding protein. The encoded protein likely plays a role in calcium homeostasis. Mutations in this gene have been associated with susceptibility to juvenile myoclonic epilepsy and juvenile absence epilepsy. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.007535279).
• BP6: Variant 6-52454252-G-A is Benign according to our data. Variant chr6-52454252-G-A is described in ClinVar as [Benign]. Clinvar id is 128970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52454252-G-A is described in Lovd as [Likely_benign]. Variant chr6-52454252-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 1437 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.881G>A	p.Arg294His	missense_variant	5/11	ENST00000371068.11
EFHC1	NM_001172420.2	c.824G>A	p.Arg275His	missense_variant	6/12
EFHC1	NR_033327.2	n.2207G>A		non_coding_transcript_exon_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.881G>A	p.Arg294His	missense_variant	5/11	1	NM_018100.4	P1

Frequencies

GnomAD3 genomes AF: 0.00945 AC: 1437 AN: 152138 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0400

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.0101 AC: 2527 AN: 251420 Hom.: 31 AF XY: 0.0105 AC XY: 1421 AN XY: 135878

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00474

Gnomad FIN exome AF: 0.0390

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00913

GnomAD4 exome AF: 0.0109 AC: 15941 AN: 1461842 Hom.: 122 Cov.: 34 AF XY: 0.0108 AC XY: 7849 AN XY: 727220

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00499

Gnomad4 FIN exome AF: 0.0393

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00974

GnomAD4 genome AF: 0.00943 AC: 1436 AN: 152256 Hom.: 13 Cov.: 32 AF XY: 0.0108 AC XY: 805 AN XY: 74448

Gnomad4 AFR AF: 0.00229

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0400

Gnomad4 NFE AF: 0.0117

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.0103 Hom.: 13

Bravo AF: 0.00638

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0106 AC: 91

ExAC AF: 0.00974 AC: 1183

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00878

EpiControl AF: 0.00954

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Juvenile myoclonic epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 19, 2017

- -

Absence seizure;C1850778:Myoclonic epilepsy, juvenile, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;.;.;T;T;T;T;T;T;.;T;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D;D;D;D;D;D;.;D
MetaRNN	Benign	0.0075	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.62	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
Polyphen		1.0	.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.98, 0.97
MPC		0.52
ClinPred		0.073	T
GERP RS		5.9
Varity_R		0.82
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1570624; hg19: chr6-52319050;