rs17851770

chr6-52492273-A-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_018100.4(EFHC1):c.1855A>C(p.Ile619Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.082 in 1,613,132 control chromosomes in the GnomAD database, including 6,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. I619S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.061 (447 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5999 hom.)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.88

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-52492274-T-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.001735568).
• BP6: Variant 6-52492273-A-C is Benign according to our data. Variant chr6-52492273-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 128966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52492273-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.1855A>C	p.Ile619Leu	missense_variant	11/11	ENST00000371068.11
EFHC1	NM_001172420.2	c.1798A>C	p.Ile600Leu	missense_variant	12/12
EFHC1	NR_033327.2	n.3181A>C		non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.1855A>C	p.Ile619Leu	missense_variant	11/11	1	NM_018100.4	P1

Frequencies

GnomAD3 genomes AF: 0.0611 AC: 9294 AN: 152128 Hom.: 448 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0923

Gnomad OTH AF: 0.0484

GnomAD3 exomes AF: 0.0619 AC: 15553 AN: 251068 Hom.: 701 AF XY: 0.0621 AC XY: 8433 AN XY: 135742

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.0258

Gnomad ASJ exome AF: 0.0774

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0173

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.0888

Gnomad OTH exome AF: 0.0618

GnomAD4 exome AF: 0.0842 AC: 122982 AN: 1460886 Hom.: 5999 Cov.: 32 AF XY: 0.0820 AC XY: 59623 AN XY: 726758

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.0275

Gnomad4 ASJ exome AF: 0.0741

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0182

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.0960

Gnomad4 OTH exome AF: 0.0751

GnomAD4 genome AF: 0.0610 AC: 9290 AN: 152246 Hom.: 447 Cov.: 32 AF XY: 0.0602 AC XY: 4480 AN XY: 74438

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.0322

Gnomad4 ASJ AF: 0.0778

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.0922

Gnomad4 OTH AF: 0.0479

Alfa AF: 0.0798 Hom.: 1141

Bravo AF: 0.0539

TwinsUK AF: 0.0979 AC: 363

ALSPAC AF: 0.0950 AC: 366

ESP6500AA AF: 0.0179 AC: 79

ESP6500EA AF: 0.0921 AC: 792

ExAC AF: 0.0622 AC: 7556

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0809

EpiControl AF: 0.0777

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Juvenile myoclonic epilepsy Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	17
Dann	Benign	0.96
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.68	T;.;T;T;T;.;T
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.72	D;D;D
PrimateAI	Uncertain	0.62	T
Polyphen		0.0030	.;.;B;.;.;.;.
Vest4		0.24, 0.15
MPC		0.087
ClinPred		0.0062	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.26

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: rs17851770; hg19: chr6-52357071; COSMIC: COSV64136428; COSMIC: COSV64136428;