rs1570624

Positions:

chr6-52454252-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

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 (★★).

Frequency

Genomes: 𝑓 0.0094 ( 13 hom., cov: 32)

Exomes 𝑓: 0.011 ( 122 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.04

Variant links:

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]

EFHC1 links:

EFHC1 (HGNC:):

EFHC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 1436 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHC1	NM_018100.4 linkuse as main transcript	c.881G>A	p.Arg294His	missense_variant	5/11	ENST00000371068.11	NP_060570.2	Q5JVL4-1B2CKC5
EFHC1	NM_001172420.2 linkuse as main transcript	c.824G>A	p.Arg275His	missense_variant	6/12		NP_001165891.1	Q5JVL4-3B2CKC5
EFHC1	NR_033327.2 linkuse as main transcript	n.2207G>A		non_coding_transcript_exon_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11 linkuse as main transcript	c.881G>A	p.Arg294His	missense_variant	5/11	1	NM_018100.4	ENSP00000360107.4		Q5JVL4-1

Frequencies

GnomAD3 genomes

AF:

0.00945

AC:

1437

AN:

152138

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0105

AC XY:

1421

AN XY:

135878

show subpopulations

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.:

AF XY:

0.0108

AC XY:

7849

AN XY:

727220

show subpopulations

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.:

Cov.:

AF XY:

0.0108

AC XY:

805

AN XY:

74448

show subpopulations

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.:

Bravo

AF:

0.00638

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.00974

AC:

1183

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00878

EpiControl

AF:

0.00954

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

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

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

MutationAssessor

Pathogenic

3.8

.;.;.;H;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-4.6

.;.;.;D;.;.;.;.;.;.;.;.;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

.;.;.;D;.;.;.;.;.;.;.;.;D

Sift4G

Pathogenic

0.0

.;.;.;D;.;.;.;.;.;.;.;.;D

Polyphen

1.0

.;.;.;D;.;.;.;.;.;.;.;.;.

Vest4

0.98, 0.97

MPC

0.52

ClinPred

0.073

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over