dbSNP rs3804506: EFHC1:p.Arg159Gly (chr6-52438493-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018100.4(EFHC1):c.475C>G(p.Arg159Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,906 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. R159Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0099 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 20 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.03

Publications

35 publications found

Variant links:

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

EFHC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.002821058).

BP6

Variant 6-52438493-C-G is Benign according to our data. Variant chr6-52438493-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196484.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 = 0.00987 (1502/152156) while in subpopulation AFR AF = 0.0347 (1442/41510). AF 95% confidence interval is 0.0332. There are 18 homozygotes in GnomAd4. There are 660 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1502 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018100.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFHC1	NM_018100.4	MANE Select	c.475C>G	p.Arg159Gly	missense	Exon 3 of 11	NP_060570.2	Q5JVL4-1
EFHC1	NM_001172420.2		c.418C>G	p.Arg140Gly	missense	Exon 4 of 12	NP_001165891.1	Q5JVL4-3
EFHC1	NR_033327.2		n.544C>G		non_coding_transcript_exon	Exon 3 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFHC1	ENST00000371068.11	TSL:1 MANE Select	c.475C>G	p.Arg159Gly	missense	Exon 3 of 11	ENSP00000360107.4	Q5JVL4-1
EFHC1	ENST00000637340.1	TSL:1	n.1143C>G		non_coding_transcript_exon	Exon 3 of 10
EFHC1	ENST00000637353.1	TSL:5	c.475C>G	p.Arg159Gly	missense	Exon 3 of 11	ENSP00000490441.1	A0A1B0GVB0

Frequencies

GnomAD3 genomes

AF:

0.00986

AC:

1499

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0348

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00528

GnomAD2 exomes

AF:

0.00274

AC:

688

AN:

251084

AF XY:

0.00189

show subpopulations

Gnomad AFR exome

AF:

0.0378

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000981

GnomAD4 exome

AF:

0.00102

AC:

1489

AN:

1461750

Hom.:

Cov.:

AF XY:

0.000894

AC XY:

650

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.0363

AC:

1214

AN:

33474

American (AMR)

AF:

0.00222

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111948

Other (OTH)

AF:

0.00220

AC:

133

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

173

260

346

433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00987

AC:

1502

AN:

152156

Hom.:

Cov.:

AF XY:

0.00887

AC XY:

660

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0347

AC:

1442

AN:

41510

American (AMR)

AF:

0.00275

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

67994

Other (OTH)

AF:

0.00522

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

161

241

322

402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000250

Hom.:

3557

ExAC

AF:

0.00360

AC:

437

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

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

EFHC1-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.028

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

1.0

PrimateAI

Benign

0.18

PROVEAN

Benign

-2.2

REVEL

Benign

0.096

Sift

Benign

0.33

Sift4G

Benign

0.33

Polyphen

0.0010

Vest4

0.21

MVP

0.67

MPC

0.11

ClinPred

0.0042

GERP RS

2.7

PromoterAI

0.00060

Neutral

(source)

Varity_R

0.085

gMVP

0.27

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over