rs145754721
Variant names:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_018100.4(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).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00044 ( 4 hom. )
Consequence
EFHC1
NM_018100.4 missense
NM_018100.4 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 3.34
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]
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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: {Uncertain_significance=2, Benign=1, Likely_benign=2}.
BS2
High AC in GnomAd4 at 25 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EFHC1 | NM_018100.4 | c.779G>A | p.Arg260Gln | missense_variant | Exon 5 of 11 | ENST00000371068.11 | NP_060570.2 | |
EFHC1 | NM_001172420.2 | c.722G>A | p.Arg241Gln | missense_variant | Exon 6 of 12 | NP_001165891.1 | ||
EFHC1 | NR_033327.2 | n.2105G>A | non_coding_transcript_exon_variant | Exon 4 of 10 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000165 AC: 25AN: 151972Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000370 AC: 93AN: 251404Hom.: 2 AF XY: 0.000464 AC XY: 63AN XY: 135866
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GnomAD4 exome AF: 0.000439 AC: 642AN: 1461848Hom.: 4 Cov.: 34 AF XY: 0.000507 AC XY: 369AN XY: 727228
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GnomAD4 genome AF: 0.000164 AC: 25AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74384
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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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;D;T;T;T;T;T;.;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
.;.;.;M;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
.;.;.;D;.;.;.;.;.;.;.;.;D
REVEL
Uncertain
Sift
Benign
.;.;.;D;.;.;.;.;.;.;.;.;D
Sift4G
Uncertain
.;.;.;D;.;.;.;.;.;.;.;.;D
Polyphen
0.43
.;.;.;B;.;.;.;.;.;.;.;.;.
Vest4
0.21, 0.20
MVP
0.80
MPC
0.12
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at