rs373196171

Positions:

chr6-52479127-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_018100.4(EFHC1):c.1369C>T(p.Arg457Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 1 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.45

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 Likely_benign. Variant got -4 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

BP4

Computational evidence support a benign effect (MetaRNN=0.25755262).

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHC1	NM_018100.4 linkuse as main transcript	c.1369C>T	p.Arg457Cys	missense_variant	8/11	ENST00000371068.11	NP_060570.2	Q5JVL4-1B2CKC5
EFHC1	NM_001172420.2 linkuse as main transcript	c.1312C>T	p.Arg438Cys	missense_variant	9/12		NP_001165891.1	Q5JVL4-3B2CKC5
EFHC1	NR_033327.2 linkuse as main transcript	n.2695C>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.1369C>T	p.Arg457Cys	missense_variant	8/11	1	NM_018100.4	ENSP00000360107.4		Q5JVL4-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251324

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000369

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000151

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 411569). This variant has not been reported in the literature in individuals affected with EFHC1-related conditions. This variant is present in population databases (rs373196171, gnomAD 0.04%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 457 of the EFHC1 protein (p.Arg457Cys). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

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

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.078

MetaRNN

Benign

0.26

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

MetaSVM

Benign

-0.68

MutationAssessor

Pathogenic

3.0

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

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.7

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

REVEL

Uncertain

0.29

Sift

Uncertain

0.025

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

Sift4G

Uncertain

0.033

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

Polyphen

0.98

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

Vest4

0.50, 0.48

MVP

0.80

MPC

0.36

ClinPred

0.60

GERP RS

1.9

Varity_R

0.50

gMVP

0.71

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