rs149055334

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.229C>A(p.Pro77Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,614,090 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 21 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 12 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.485

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=0.00282076).

BP6

Variant 6-52424111-C-A is Benign according to our data. Variant chr6-52424111-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 205400.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 = 0.00719 (1095/152218) while in subpopulation AFR AF= 0.0249 (1032/41528). AF 95% confidence interval is 0.0236. 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 1095 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EFHC1	NM_018100.4 linkuse as main transcript	c.229C>A	p.Pro77Thr	missense_variant	2/11	ENST00000371068.11
EFHC1	NM_001172420.2 linkuse as main transcript	c.172C>A	p.Pro58Thr	missense_variant	3/12
EFHC1	NR_033327.2 linkuse as main transcript	n.298C>A		non_coding_transcript_exon_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11 linkuse as main transcript	c.229C>A	p.Pro77Thr	missense_variant	2/11	1	NM_018100.4	P1	Q5JVL4-1

Frequencies

GnomAD3 genomes

AF:

0.00721

AC:

1096

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00194

AC:

488

AN:

251438

Hom.:

AF XY:

0.00159

AC XY:

216

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0255

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000690

AC:

1008

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000620

AC XY:

451

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0243

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00719

AC:

1095

AN:

152218

Hom.:

Cov.:

AF XY:

0.00685

AC XY:

510

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0249

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.00863

ESP6500AA

AF:

0.0243

AC:

107

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00235

AC:

285

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -
not provided, no classification provided	clinical testing	GeneDx	Apr 03, 2015	p.Pro77Thr (CCT>ACT): c.229 C>A in exon 2 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	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -
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:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 22, 2022	- -
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

0.077

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.057

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

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.057

LIST_S2

Uncertain

0.90

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

MetaRNN

Benign

0.0028

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

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

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.51

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

REVEL

Benign

0.12

Sift

Benign

0.55

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

Sift4G

Benign

0.61

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

Polyphen

0.0

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

Vest4

0.28, 0.24

MVP

0.54

MPC

0.096

ClinPred

0.0060

GERP RS

3.1

Varity_R

0.098

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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