rs369503191

Positions:

chr6-52490311-A-C

Variant summary

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

The NM_018100.4(EFHC1):c.1812A>C(p.Glu604Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000716 in 1,614,168 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 31 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.204

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033372045).

BP6

Variant 6-52490311-A-C is Benign according to our data. Variant chr6-52490311-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128964.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=3}.

BS2

High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHC1	NM_018100.4 linkuse as main transcript	c.1812A>C	p.Glu604Asp	missense_variant	10/11	ENST00000371068.11	NP_060570.2	Q5JVL4-1B2CKC5
EFHC1	NM_001172420.2 linkuse as main transcript	c.1755A>C	p.Glu585Asp	missense_variant	11/12		NP_001165891.1	Q5JVL4-3B2CKC5
EFHC1	NR_033327.2 linkuse as main transcript	n.3138A>C		non_coding_transcript_exon_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11 linkuse as main transcript	c.1812A>C	p.Glu604Asp	missense_variant	10/11	1	NM_018100.4	ENSP00000360107.4		Q5JVL4-1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00703

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00146

AC:

366

AN:

251176

Hom.:

AF XY:

0.00192

AC XY:

260

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0114

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000760

AC:

1111

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

789

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0115

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.000977

GnomAD4 genome

AF:

0.000295

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00174

AC:

211

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 02, 2013	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2015	- -

Juvenile myoclonic epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

9.9

DANN

Benign

0.88

DEOGEN2

Benign

0.061

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

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.68

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

MetaRNN

Benign

0.0033

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.060

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

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.020

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

REVEL

Benign

0.031

Sift

Benign

0.75

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

Sift4G

Benign

0.65

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

Polyphen

0.0

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

Vest4

0.12, 0.11

MutPred

0.32

.;.;Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);.;Gain of helix (P = 0.2059);.;.;.;

MVP

0.46

MPC

0.077

ClinPred

0.0087

GERP RS

0.67

Varity_R

0.029

gMVP

0.17

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