rs137852776

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_018100.4(EFHC1):c.685T>C(p.Phe229Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0033 in 1,614,032 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 25 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 4.61

Publications

27 publications found

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 Gene-Disease associations (from GenCC):

juvenile myoclonic epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

EFHC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008032471).

BP6

Variant 6-52452799-T-C is Benign according to our data. Variant chr6-52452799-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2064.

BS2

High AC in GnomAd4 at 378 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHC1	NM_018100.4 link	c.685T>C	p.Phe229Leu	missense_variant	Exon 4 of 11	ENST00000371068.11	NP_060570.2	Q5JVL4-1B2CKC5
EFHC1	NM_001172420.2 link	c.628T>C	p.Phe210Leu	missense_variant	Exon 5 of 12		NP_001165891.1	Q5JVL4-3B2CKC5
EFHC1	NR_033327.2 link	n.754T>C		non_coding_transcript_exon_variant	Exon 4 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11 link	c.685T>C	p.Phe229Leu	missense_variant	Exon 4 of 11	1	NM_018100.4	ENSP00000360107.4		Q5JVL4-1

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

381

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00372

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.00349

AC:

878

AN:

251444

AF XY:

0.00389

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00734

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00446

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00338

AC:

4947

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

2624

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33480

American (AMR)

AF:

0.00226

AC:

101

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00930

AC:

243

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00639

AC:

551

AN:

86258

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.0175

AC:

101

AN:

5768

European-Non Finnish (NFE)

AF:

0.00325

AC:

3616

AN:

1111862

Other (OTH)

AF:

0.00492

AC:

297

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

313

625

938

1250

1563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00248

AC:

378

AN:

152324

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

164

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41578

American (AMR)

AF:

0.00268

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5190

South Asian (SAS)

AF:

0.00311

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00372

AC:

253

AN:

68016

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00382

Hom.:

Bravo

AF:

0.00299

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00358

AC:

434

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00480

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23527921, 22690745, 27467453, 17634063, 17159113, 25625532, 28370826, 25489633, 24965021, 22226147, 18823326, 12439895, 15258581, 22926142) -

Apr 04, 2019

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EFHC1: BS2 -

not specified

Uncertain:1Benign:1

Jun 18, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 05, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Absence seizure

Uncertain:1

Jul 02, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myoclonic epilepsy, juvenile, susceptibility to, 1

Uncertain:1

Dec 12, 2006

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.058

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

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

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

M_CAP

Benign

0.031

MetaRNN

Benign

0.0080

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

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.1

.;.;.;M;.;.;.;.;.;.;.;.;.

PhyloP100

4.6

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.6

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

REVEL

Uncertain

0.40

Sift

Benign

0.12

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

Sift4G

Benign

0.46

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

Polyphen

0.50

.;.;.;P;.;.;.;.;.;.;.;.;.

Vest4

0.55, 0.54

MutPred

0.72

.;.;.;Gain of ubiquitination at K233 (P = 0.1084);Gain of ubiquitination at K233 (P = 0.1084);Gain of ubiquitination at K233 (P = 0.1084);Gain of ubiquitination at K233 (P = 0.1084);Gain of ubiquitination at K233 (P = 0.1084);.;Gain of ubiquitination at K233 (P = 0.1084);.;.;.;

MVP

0.73

MPC

0.12

ClinPred

0.043

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.57

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over