rs377286138

Positions:

chr6-52479064-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2

The NM_018100.4(EFHC1):c.1306C>T(p.Arg436Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.67

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain DM10 3 (size 104) in uniprot entity EFHC1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_018100.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHC1	NM_018100.4 linkuse as main transcript	c.1306C>T	p.Arg436Cys	missense_variant	8/11	ENST00000371068.11	NP_060570.2	Q5JVL4-1B2CKC5
EFHC1	NM_001172420.2 linkuse as main transcript	c.1249C>T	p.Arg417Cys	missense_variant	9/12		NP_001165891.1	Q5JVL4-3B2CKC5
EFHC1	NR_033327.2 linkuse as main transcript	n.2632C>T		non_coding_transcript_exon_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11 linkuse as main transcript	c.1306C>T	p.Arg436Cys	missense_variant	8/11	1	NM_018100.4	ENSP00000360107.4		Q5JVL4-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251322

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000109

AC:

160

AN:

1461650

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000111

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2013	p.Arg436Cys (R436C) CGC>TGC: c.1306 C>T in exon 8 of the EFHC1 gene (NM_018100.3). The Arg436Cys missense change in the EFHC1 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged Cysteine residue, and the addition of a Cysteine may affect disulfide bonding and the secondary structure of the protein. The variant alters a conserved position in the DM10-3 domain of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, based on the currently available information, it is unclear whether Arg436Cys is a disease-causing mutation or a rare benign variant.Therefore, based on the currently available information, it is unclear whether R436C is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2014	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 436 of the EFHC1 protein (p.Arg436Cys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on EFHC1 function (PMID: 28370826). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EFHC1 protein function. ClinVar contains an entry for this variant (Variation ID: 198888). This missense change has been observed in individual(s) with myoclonic epilepsy (PMID: 28370826; Invitae). This variant is present in population databases (rs377286138, gnomAD 0.03%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

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

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-7.9

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

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.99, 0.98

MVP

1.0

MPC

0.54

ClinPred

0.99

GERP RS

5.9

Varity_R

0.95

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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