rs200116252
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_018100.4(EFHC1):āc.1385T>Cā(p.Ile462Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0001 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: š 0.000085 ( 0 hom., cov: 32)
Exomes š: 0.00010 ( 0 hom. )
Consequence
EFHC1
NM_018100.4 missense
NM_018100.4 missense
Scores
6
8
Clinical Significance
Conservation
PhyloP100: 4.88
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM1
?
In a domain DM10 3 (size 104) in uniprot entity EFHC1_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_018100.4
BP4
?
Computational evidence support a benign effect (MetaRNN=0.31056187).
BS2
?
High AC in GnomAd4 at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EFHC1 | NM_018100.4 | c.1385T>C | p.Ile462Thr | missense_variant | 8/11 | ENST00000371068.11 | |
EFHC1 | NM_001172420.2 | c.1328T>C | p.Ile443Thr | missense_variant | 9/12 | ||
EFHC1 | NR_033327.2 | n.2711T>C | non_coding_transcript_exon_variant | 7/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EFHC1 | ENST00000371068.11 | c.1385T>C | p.Ile462Thr | missense_variant | 8/11 | 1 | NM_018100.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152168Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
13
AN:
152168
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000163 AC: 41AN: 251340Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135830
GnomAD3 exomes
AF:
AC:
41
AN:
251340
Hom.:
AF XY:
AC XY:
25
AN XY:
135830
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000102 AC: 149AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.000118 AC XY: 86AN XY: 727220
GnomAD4 exome
AF:
AC:
149
AN:
1461838
Hom.:
Cov.:
32
AF XY:
AC XY:
86
AN XY:
727220
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152286Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74472
GnomAD4 genome
?
AF:
AC:
13
AN:
152286
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74472
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
1
ALSPAC
AF:
AC:
0
ExAC
?
AF:
AC:
29
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2015 | The I462T variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I462T 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. This substitution occurs at a position that is conserved across species. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with EFHC1-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 24, 2013 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2023 | The c.1385T>C (p.I462T) alteration is located in exon 8 (coding exon 8) of the EFHC1 gene. This alteration results from a T to C substitution at nucleotide position 1385, causing the isoleucine (I) at amino acid position 462 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Absence seizure;C0270853:Juvenile myoclonic epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Absence seizure;C1850778:Myoclonic epilepsy, juvenile, susceptibility to, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;T;T;T;T;T;T;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
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
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Polyphen
0.37
.;.;.;B;.;.;.;.;.;.;.;.;.
Vest4
0.29, 0.25
MVP
0.70
MPC
0.43
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at