rs79761183

chr6-52452776-G-Achr6-52452776-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018100.4(EFHC1):c.662G>A(p.Arg221His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,130 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R221C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0071 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (11 hom.)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.94

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005691111).
• BP6: Variant 6-52452776-G-A is Benign according to our data. Variant chr6-52452776-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 205384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0071 (1081/152274) while in subpopulation AFR AF= 0.0245 (1017/41534). AF 95% confidence interval is 0.0232. There are 21 homozygotes in gnomad4. There are 510 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1082 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.662G>A	p.Arg221His	missense_variant	4/11	ENST00000371068.11
EFHC1	NM_001172420.2	c.605G>A	p.Arg202His	missense_variant	5/12
EFHC1	NR_033327.2	n.731G>A		non_coding_transcript_exon_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.662G>A	p.Arg221His	missense_variant	4/11	1	NM_018100.4	P1

Frequencies

GnomAD3 genomes AF: 0.00711 AC: 1082 AN: 152156 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00197 AC: 495 AN: 251412 Hom.: 7 AF XY: 0.00161 AC XY: 219 AN XY: 135866

Gnomad AFR exome AF: 0.0254

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000716 AC: 1046 AN: 1461856 Hom.: 11 Cov.: 32 AF XY: 0.000656 AC XY: 477 AN XY: 727232

Gnomad4 AFR exome AF: 0.0239

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00710 AC: 1081 AN: 152274 Hom.: 21 Cov.: 32 AF XY: 0.00685 AC XY: 510 AN XY: 74452

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000515 Hom.: 1

Bravo AF: 0.00854

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00234 AC: 284

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	clinical testing	GeneDx	Apr 03, 2015	p.Arg221His (CGT>CAT): c.662 G>A in exon 4 of the EFHC1 gene (NM_018100.3). P77T and R221H were identified on the same chromosome and co-segregated with juvenile myoclonic epilepsy (JME) in two families (Suzuki et al., 2004). Functional studies suggest that both P77T and R221H impair apoptosis and alter calcium currents (Suzuki et al., 2004). However, both P77T and R221H have subsequently been identified in 1-3% of the African population in the NHLBI ESP Exome Variant Project and the 1000 Genomes Database. P77T results in a nonconservative amino acid substitution, while the R221H substitution is a conservative change. Both of these missense substitutions alter positions in the protein that are not highly conserved throughout evolution or in related proteins, and multiple in silico models predict they are likely benign. Therefore, currently available evidence suggests that P77T and R221H may be associated with JME, although the possibility that they are benign variants cannot be completely excluded. The variant is found in CHILD-EPI,EPILEPSY,INFANT-EPI panel(s). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2016	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

EFHC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 30, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.032	T;.;.;T;T;T;T;T;T;.;T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.92	D;D;.;D;D;D;D;D;D;D;D;.;D
MetaRNN	Benign	0.0057	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
Polyphen		0.043	.;.;.;B;.;.;.;.;.;.;.;.;.
Vest4		0.22, 0.24
MVP		0.77
MPC		0.11
ClinPred		0.011	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.48

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

Other links and lift over

dbSNP: rs79761183; hg19: chr6-52317574;