Genetic Variant EFHC1:p.Arg221His (chr6-52452776-G-A) – 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.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. 14/21 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. 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 1.94

Publications

16 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=0.005691111).

BP6

Variant 6-52452776-G-A is Benign according to our data. Variant chr6-52452776-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1081 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.662G>A	p.Arg221His	missense	Exon 4 of 11	NP_060570.2	Q5JVL4-1
EFHC1	NM_001172420.2		c.605G>A	p.Arg202His	missense	Exon 5 of 12	NP_001165891.1	Q5JVL4-3
EFHC1	NR_033327.2		n.731G>A		non_coding_transcript_exon	Exon 4 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFHC1	ENST00000371068.11	TSL:1 MANE Select	c.662G>A	p.Arg221His	missense	Exon 4 of 11	ENSP00000360107.4	Q5JVL4-1
EFHC1	ENST00000637340.1	TSL:1	n.1330G>A		non_coding_transcript_exon	Exon 4 of 10
EFHC1	ENST00000637353.1	TSL:5	c.662G>A	p.Arg221His	missense	Exon 4 of 11	ENSP00000490441.1	A0A1B0GVB0

Frequencies

GnomAD3 genomes

AF:

0.00711

AC:

1082

AN:

152156

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00197

AC:

495

AN:

251412

AF XY:

0.00161

show subpopulations

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 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.:

Cov.:

AF XY:

0.000656

AC XY:

477

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0239

AC:

800

AN:

33480

American (AMR)

AF:

0.00199

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

1111992

Other (OTH)

AF:

0.00142

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

136

205

273

341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00710

AC:

1081

AN:

152274

Hom.:

Cov.:

AF XY:

0.00685

AC XY:

510

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0245

AC:

1017

AN:

41534

American (AMR)

AF:

0.00333

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

102

152

203

254

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:

0.00233

Hom.:

Bravo

AF:

0.00854

ESP6500AA

AF:

0.0238

AC:

105

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00234

AC:

284

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

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

EFHC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0057

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

PhyloP100

1.9

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.087

Sift

Benign

0.036

Sift4G

Uncertain

0.043

Polyphen

0.043

Vest4

0.22

MVP

0.77

MPC

0.11

ClinPred

0.011

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.059

gMVP

0.48

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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