rs3804505

chr6-52438563-G-Achr6-52438563-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018100.4(EFHC1):c.545G>A(p.Arg182His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0591 in 1,613,812 control chromosomes in the GnomAD database, including 3,170 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R182C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.048 (240 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2930 hom.)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 1.34

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028097034).
• BP6: Variant 6-52438563-G-A is Benign according to our data. Variant chr6-52438563-G-A is described in ClinVar as [Benign]. Clinvar id is 2063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52438563-G-A is described in Lovd as [Benign]. Variant chr6-52438563-G-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.545G>A	p.Arg182His	missense_variant	3/11	ENST00000371068.11
EFHC1	NM_001172420.2	c.488G>A	p.Arg163His	missense_variant	4/12
EFHC1	NR_033327.2	n.614G>A		non_coding_transcript_exon_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.545G>A	p.Arg182His	missense_variant	3/11	1	NM_018100.4	P1

Frequencies

GnomAD3 genomes AF: 0.0475 AC: 7224 AN: 152040 Hom.: 235 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0447

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.0726

Gnomad SAS AF: 0.0722

Gnomad FIN AF: 0.0897

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0597

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0603 AC: 15135 AN: 251004 Hom.: 552 AF XY: 0.0615 AC XY: 8348 AN XY: 135672

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0534

Gnomad ASJ exome AF: 0.0481

Gnomad EAS exome AF: 0.0821

Gnomad SAS exome AF: 0.0687

Gnomad FIN exome AF: 0.0870

Gnomad NFE exome AF: 0.0599

Gnomad OTH exome AF: 0.0579

GnomAD4 exome AF: 0.0602 AC: 88055 AN: 1461652 Hom.: 2930 Cov.: 33 AF XY: 0.0602 AC XY: 43806 AN XY: 727146

Gnomad4 AFR exome AF: 0.00938

Gnomad4 AMR exome AF: 0.0520

Gnomad4 ASJ exome AF: 0.0501

Gnomad4 EAS exome AF: 0.0603

Gnomad4 SAS exome AF: 0.0687

Gnomad4 FIN exome AF: 0.0893

Gnomad4 NFE exome AF: 0.0604

Gnomad4 OTH exome AF: 0.0612

GnomAD4 genome AF: 0.0476 AC: 7241 AN: 152160 Hom.: 240 Cov.: 32 AF XY: 0.0489 AC XY: 3636 AN XY: 74374

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.0449

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.0723

Gnomad4 SAS AF: 0.0729

Gnomad4 FIN AF: 0.0897

Gnomad4 NFE AF: 0.0597

Gnomad4 OTH AF: 0.0464

Alfa AF: 0.0534 Hom.: 636

Bravo AF: 0.0423

TwinsUK AF: 0.0677 AC: 251

ALSPAC AF: 0.0568 AC: 219

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.0603 AC: 519

ExAC AF: 0.0604 AC: 7329

Asia WGS AF: 0.117 AC: 404 AN: 3478

EpiCase AF: 0.0542

EpiControl AF: 0.0543

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:5

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	-	- -

Myoclonic epilepsy, juvenile, susceptibility to, 1 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 01, 2004

- -

Juvenile myoclonic epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 08, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 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	0.062
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	14
Dann	Benign	0.84
DEOGEN2	Benign	0.0042	T;.;.;T;T;T;T;T;T;.;.;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;D;.;D;D;D;D;D;D;D;.;T;D
MetaRNN	Benign	0.0028	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.21	T
Polyphen		0.0040	.;.;.;B;.;.;.;.;.;.;.;.;.
Vest4		0.047, 0.040
MPC		0.11
ClinPred		0.0026	T
GERP RS		0.80
Varity_R		0.032
gMVP		0.50

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: rs3804505; hg19: chr6-52303361; COSMIC: COSV64137554; COSMIC: COSV64137554;