rs140476054

Positions:

• chr6-52454102-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_018100.4(EFHC1):​c.731G>A​(p.Arg244Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00015 in 1,613,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.04

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771
• BP6: Variant 6-52454102-G-A is Benign according to our data. Variant chr6-52454102-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205388.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS2: High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.731G>A	p.Arg244Gln	missense_variant	5/11	ENST00000371068.11
EFHC1	NM_001172420.2	c.674G>A	p.Arg225Gln	missense_variant	6/12
EFHC1	NR_033327.2	n.2057G>A		non_coding_transcript_exon_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.731G>A	p.Arg244Gln	missense_variant	5/11	1	NM_018100.4	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000955 AC: 24 AN: 251272 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135826

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 223 AN: 1461060 Hom.: 0 Cov.: 34 AF XY: 0.000129 AC XY: 94 AN XY: 726858

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74360

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000907

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

This variant has not been reported in the literature in individuals affected with EFHC1-related conditions. 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. 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: 205388). This variant is present in population databases (rs140476054, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 244 of the EFHC1 protein (p.Arg244Gln). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 22, 2015

p.Arg244Gln (CGA>CAA): c.731 G>A in exon 5 of the EFHC1 gene (NM_018100.3). The Arg244Gln missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid substitution is non-conservative, as a positively charged Arginine residue is replaced by an uncharged Glutamine residue. Arg244Gln alters a position that is highly conserved across species and in related proteins. This variant lies within the second DM10 domain of the protein, and missense mutations altering nearby codons in this domain have been reported in association with epilepsy (Suzuki et al., 2004; Bai et al., 2009). Multiple in silico models predict Arg244Gln may be damaging to protein structure/function. Based on the available information, Arg244Gln is a candidate for a disease-causing mutation, but the possibility that it is a rare benign variant cannot be excluded. The variant is found in EPILEPSY panel(s). -

Epilepsy, idiopathic generalized, susceptibility to, 7 Benign:1

Benign, criteria provided, single submitter

research

Experimental Epileptology, AG Lerche, Hertie Institute for Clinical Brain Research

Jan 02, 2022

ACMG/AMP criteria: PP3, BS1, BS4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;.;.;D;T;T;T;T;T;.;T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
Polyphen		1.0	.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.92, 0.94
MVP		0.97
MPC		0.50
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.62
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs140476054; hg19: chr6-52318900; COSMIC: COSV64135753; COSMIC: COSV64135753;