rs17851770

Variant names:

• chr6-52492273-A-C
• rs17851770
• NM_018100.4:c.1855A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 13/21 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:7
• Conservation: PhyloP100: 1.88
• Publications: 24 publications found

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]

EFHC1 Gene-Disease associations (from GenCC):

• juvenile myoclonic epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 128966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
EFHC1	NM_018100.4	c.1855A>C	p.Ile619Leu	missense_variant	Exon 11 of 11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2	c.1798A>C	p.Ile600Leu	missense_variant	Exon 12 of 12		NP_001165891.1
EFHC1	NR_033327.2	n.3181A>C		non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11	c.1855A>C	p.Ile619Leu	missense_variant	Exon 11 of 11	1	NM_018100.4	ENSP00000360107.4

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

GnomAD2 exomes AF: 0.0619 AC: 15553 AN: 251068 AF XY: 0.0621

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 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

African (AFR) AF: 0.0123 AC: 411 AN: 33460

American (AMR) AF: 0.0275 AC: 1229 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0741 AC: 1936 AN: 26110

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39694

South Asian (SAS) AF: 0.0182 AC: 1569 AN: 86238

European-Finnish (FIN) AF: 0.122 AC: 6523 AN: 53368

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5768

European-Non Finnish (NFE) AF: 0.0960 AC: 106706 AN: 1111180

Other (OTH) AF: 0.0751 AC: 4535 AN: 60354

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

African (AFR) AF: 0.0160 AC: 664 AN: 41556

American (AMR) AF: 0.0322 AC: 492 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 270 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0129 AC: 62 AN: 4824

European-Finnish (FIN) AF: 0.122 AC: 1290 AN: 10586

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0922 AC: 6272 AN: 68008

Other (OTH) AF: 0.0479 AC: 101 AN: 2108

Alfa AF: 0.0755 Hom.: 1545

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Juvenile myoclonic epilepsy Benign:2

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Benign	0.079	.;.;T;T;T;.;.
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
MutationAssessor	Uncertain	2.2	.;.;M;.;.;.;.
PhyloP100		1.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.60	.;.;N;.;.;.;N
REVEL	Benign	0.10
Sift	Benign	0.21	.;.;T;.;.;.;T
Sift4G	Benign	0.47	.;.;T;.;.;.;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
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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