6-52492273-A-C

Position:

chr6-52492273-A-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_018100.4(EFHC1):c.1855A>C(p.Ile619Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.082 in 1,613,132 control chromosomes in the GnomAD database, including 6,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. I619S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.061 ( 447 hom., cov: 32)

Exomes 𝑓: 0.084 ( 5999 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.88

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 -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-52492274-T-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.001735568).

BP6

Variant 6-52492273-A-C is Benign according to our data. Variant chr6-52492273-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 128966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52492273-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EFHC1	NM_018100.4 linkuse as main transcript	c.1855A>C	p.Ile619Leu	missense_variant	11/11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2 linkuse as main transcript	c.1798A>C	p.Ile600Leu	missense_variant	12/12		NP_001165891.1
EFHC1	NR_033327.2 linkuse as main transcript	n.3181A>C		non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11 linkuse as main transcript	c.1855A>C	p.Ile619Leu	missense_variant	11/11	1	NM_018100.4	ENSP00000360107	P1	Q5JVL4-1

Frequencies

GnomAD3 genomes

AF:

0.0611

AC:

9294

AN:

152128

Hom.:

448

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.145

Gnomad AMR

AF:

0.0322

Gnomad ASJ

AF:

0.0778

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.122

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0923

Gnomad OTH

AF:

0.0484

GnomAD3 exomes

AF:

0.0619

AC:

15553

AN:

251068

Hom.:

701

AF XY:

0.0621

AC XY:

8433

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.0159

Gnomad AMR exome

AF:

0.0258

Gnomad ASJ exome

AF:

0.0774

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0173

Gnomad FIN exome

AF:

0.122

Gnomad NFE exome

AF:

0.0888

Gnomad OTH exome

AF:

0.0618

GnomAD4 exome

AF:

0.0842

AC:

122982

AN:

1460886

Hom.:

5999

Cov.:

AF XY:

0.0820

AC XY:

59623

AN XY:

726758

show subpopulations

Gnomad4 AFR exome

AF:

0.0123

Gnomad4 AMR exome

AF:

0.0275

Gnomad4 ASJ exome

AF:

0.0741

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0182

Gnomad4 FIN exome

AF:

0.122

Gnomad4 NFE exome

AF:

0.0960

Gnomad4 OTH exome

AF:

0.0751

GnomAD4 genome

AF:

0.0610

AC:

9290

AN:

152246

Hom.:

447

Cov.:

AF XY:

0.0602

AC XY:

4480

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0160

Gnomad4 AMR

AF:

0.0322

Gnomad4 ASJ

AF:

0.0778

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0129

Gnomad4 FIN

AF:

0.122

Gnomad4 NFE

AF:

0.0922

Gnomad4 OTH

AF:

0.0479

Alfa

AF:

0.0798

Hom.:

1141

Bravo

AF:

0.0539

TwinsUK

AF:

0.0979

AC:

363

ALSPAC

AF:

0.0950

AC:

366

ESP6500AA

AF:

0.0179

AC:

ESP6500EA

AF:

0.0921

AC:

792

ExAC

AF:

0.0622

AC:

7556

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0809

EpiControl

AF:

0.0777

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Juvenile myoclonic epilepsy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.079

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

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.68

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

MetaRNN

Benign

0.0017

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

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

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

MutationTaster

Benign

0.72

D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.60

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

REVEL

Benign

0.10

Sift

Benign

0.21

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

Sift4G

Benign

0.47

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

Polyphen

0.0030

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

Vest4

0.24, 0.15

MPC

0.087

ClinPred

0.0062

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.26

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