chr6-52454150-G-A

Position:

chr6-52454150-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000371068.11(EFHC1):c.779G>A(p.Arg260Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 1,613,938 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R260W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 4 hom. )

Consequence

EFHC1
ENST00000371068.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 3.34

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02030781).

BP6

Variant 6-52454150-G-A is Benign according to our data. Variant chr6-52454150-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205389.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2, Likely_benign=2}.

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EFHC1	NM_018100.4 linkuse as main transcript	c.779G>A	p.Arg260Gln	missense_variant	5/11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2 linkuse as main transcript	c.722G>A	p.Arg241Gln	missense_variant	6/12		NP_001165891.1
EFHC1	NR_033327.2 linkuse as main transcript	n.2105G>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.779G>A	p.Arg260Gln	missense_variant	5/11	1	NM_018100.4	ENSP00000360107	P1	Q5JVL4-1

Frequencies

GnomAD3 genomes

AF:

0.000165

AC:

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000370

AC:

AN:

251404

Hom.:

AF XY:

0.000464

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00180

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000439

AC:

642

AN:

1461848

Hom.:

Cov.:

AF XY:

0.000507

AC XY:

369

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00179

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000412

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000164

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000289

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2024	Variant summary: EFHC1 c.779G>A (p.Arg260Gln) results in a conservative amino acid change located in the DM10 domain (IPR006602) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 1613938 control chromosomes, predominantly at a frequency of 0.0018 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes (gnomAD v4.1.0). c.779G>A has been reported in the literature in at least an individual affected with Juvenile Myoclonic Epilepsy (example: Thounaojam_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Juvenile Myoclonic Epilepsy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34426522, 29750216). ClinVar contains an entry for this variant (Variation ID: 205389). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 09, 2017	- -

Juvenile myoclonic epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 21, 2015

p.Arg260Gln (CGG>CAG): c.779 G>A in exon 5 of the EFHC1 gene (NM_018100.3). The R260Q variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R260Q variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not highly conserved across species within the second DM10 domain of the protein and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2022

- -

EFHC1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2020

This variant is classified as likely 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

0.094

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

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

Eigen

Benign

0.17

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.92

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

M_CAP

Benign

0.038

MetaRNN

Benign

0.020

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

MetaSVM

Benign

-0.64

MutationAssessor

Pathogenic

3.4

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

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.6

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

REVEL

Uncertain

0.30

Sift

Benign

0.038

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

Sift4G

Uncertain

0.013

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

Polyphen

0.43

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

Vest4

0.21, 0.20

MVP

0.80

MPC

0.12

ClinPred

0.16

GERP RS

4.1

Varity_R

0.17

gMVP

0.63

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