rs79761183

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018100.4(EFHC1):c.662G>A(p.Arg221His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,130 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R221C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0071 ( 21 hom., cov: 32)

Exomes 𝑓: 0.00072 ( 11 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 1.94

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005691111).

BP6

Variant 6-52452776-G-A is Benign according to our data. Variant chr6-52452776-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 205384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0071 (1081/152274) while in subpopulation AFR AF= 0.0245 (1017/41534). AF 95% confidence interval is 0.0232. There are 21 homozygotes in gnomad4. There are 510 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1081 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EFHC1	NM_018100.4 linkuse as main transcript	c.662G>A	p.Arg221His	missense_variant	4/11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2 linkuse as main transcript	c.605G>A	p.Arg202His	missense_variant	5/12		NP_001165891.1
EFHC1	NR_033327.2 linkuse as main transcript	n.731G>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.662G>A	p.Arg221His	missense_variant	4/11	1	NM_018100.4	ENSP00000360107	P1	Q5JVL4-1

Frequencies

GnomAD3 genomes

AF:

0.00711

AC:

1082

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00197

AC:

495

AN:

251412

Hom.:

AF XY:

0.00161

AC XY:

219

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.0254

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000716

AC:

1046

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000656

AC XY:

477

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0239

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.00142

GnomAD4 genome

AF:

0.00710

AC:

1081

AN:

152274

Hom.:

Cov.:

AF XY:

0.00685

AC XY:

510

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0245

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.000515

Hom.:

Bravo

AF:

0.00854

ESP6500AA

AF:

0.0238

AC:

105

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00234

AC:

284

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -
not provided, no classification provided	clinical testing	GeneDx	Apr 03, 2015	p.Arg221His (CGT>CAT): c.662 G>A in exon 4 of the EFHC1 gene (NM_018100.3). P77T and R221H were identified on the same chromosome and co-segregated with juvenile myoclonic epilepsy (JME) in two families (Suzuki et al., 2004). Functional studies suggest that both P77T and R221H impair apoptosis and alter calcium currents (Suzuki et al., 2004). However, both P77T and R221H have subsequently been identified in 1-3% of the African population in the NHLBI ESP Exome Variant Project and the 1000 Genomes Database. P77T results in a nonconservative amino acid substitution, while the R221H substitution is a conservative change. Both of these missense substitutions alter positions in the protein that are not highly conserved throughout evolution or in related proteins, and multiple in silico models predict they are likely benign. Therefore, currently available evidence suggests that P77T and R221H may be associated with JME, although the possibility that they are benign variants cannot be completely excluded. The variant is found in CHILD-EPI,EPILEPSY,INFANT-EPI panel(s). -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2016	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

EFHC1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 30, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

T;.;.;T;T;T;T;T;T;.;T;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.92

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

MetaRNN

Benign

0.0057

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

.;.;.;L;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.5

.;.;.;N;.;.;.;.;.;.;.;.;N

REVEL

Benign

0.087

Sift

Benign

0.036

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

Sift4G

Uncertain

0.043

.;.;.;D;.;.;.;.;.;.;.;.;T

Polyphen

0.043

.;.;.;B;.;.;.;.;.;.;.;.;.

Vest4

0.22, 0.24

MVP

0.77

MPC

0.11

ClinPred

0.011

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.059

gMVP

0.48

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

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