NM_018100.4:c.475C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018100.4(EFHC1):c.475C>T(p.Arg159Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,778 control chromosomes in the GnomAD database, including 11,090 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. R159Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.098 ( 821 hom., cov: 32)

Exomes 𝑓: 0.11 ( 10269 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

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

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=0.0014902949).

BP6

Variant 6-52438493-C-T is Benign according to our data. Variant chr6-52438493-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

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>T	p.Arg159Trp	missense	Exon 3 of 11	NP_060570.2	Q5JVL4-1
EFHC1	NM_001172420.2		c.418C>T	p.Arg140Trp	missense	Exon 4 of 12	NP_001165891.1	Q5JVL4-3
EFHC1	NR_033327.2		n.544C>T		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>T	p.Arg159Trp	missense	Exon 3 of 11	ENSP00000360107.4	Q5JVL4-1
EFHC1	ENST00000637340.1	TSL:1	n.1143C>T		non_coding_transcript_exon	Exon 3 of 10
EFHC1	ENST00000638075.1	TSL:4	c.-144C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 5	ENSP00000490711.1	A0A1B0GVZ5

Frequencies

GnomAD3 genomes

AF:

0.0979

AC:

14878

AN:

152016

Hom.:

823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0554

Gnomad AMI

AF:

0.211

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.140

Gnomad EAS

AF:

0.0375

Gnomad SAS

AF:

0.0776

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.123

GnomAD2 exomes

AF:

0.102

AC:

25501

AN:

251084

AF XY:

0.104

show subpopulations

Gnomad AFR exome

AF:

0.0515

Gnomad AMR exome

AF:

0.0772

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.0362

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.127

Gnomad OTH exome

AF:

0.119

GnomAD4 exome

AF:

0.114

AC:

166554

AN:

1461644

Hom.:

10269

Cov.:

AF XY:

0.114

AC XY:

82864

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.0547

AC:

1832

AN:

33472

American (AMR)

AF:

0.0798

AC:

3567

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

3679

AN:

26130

East Asian (EAS)

AF:

0.0430

AC:

1705

AN:

39694

South Asian (SAS)

AF:

0.0827

AC:

7132

AN:

86256

European-Finnish (FIN)

AF:

0.101

AC:

5386

AN:

53400

Middle Eastern (MID)

AF:

0.232

AC:

1337

AN:

5768

European-Non Finnish (NFE)

AF:

0.122

AC:

135212

AN:

1111850

Other (OTH)

AF:

0.111

AC:

6704

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

8077

16153

24230

32306

40383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4770

9540

14310

19080

23850

<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:

0.0978

AC:

14882

AN:

152134

Hom.:

821

Cov.:

AF XY:

0.0984

AC XY:

7321

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0553

AC:

2296

AN:

41504

American (AMR)

AF:

0.102

AC:

1565

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

486

AN:

3466

East Asian (EAS)

AF:

0.0374

AC:

194

AN:

5188

South Asian (SAS)

AF:

0.0777

AC:

375

AN:

4826

European-Finnish (FIN)

AF:

0.106

AC:

1117

AN:

10572

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.122

AC:

8326

AN:

67980

Other (OTH)

AF:

0.123

AC:

260

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

696

1392

2089

2785

3481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<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:

0.116

Hom.:

3557

Bravo

AF:

0.0980

TwinsUK

AF:

0.118

AC:

438

ALSPAC

AF:

0.125

AC:

482

ESP6500AA

AF:

0.0563

AC:

248

ESP6500EA

AF:

0.123

AC:

1057

ExAC

AF:

0.100

AC:

12170

EpiCase

AF:

0.135

EpiControl

AF:

0.138

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Juvenile myoclonic epilepsy (2)

not provided (2)

not specified (2)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

-0.036

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.12

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.4

PhyloP100

1.0

PrimateAI

Benign

0.19

PROVEAN

Benign

-2.3

REVEL

Benign

0.18

Sift

Benign

0.18

Sift4G

Benign

0.18

Polyphen

0.96

Vest4

0.18

MPC

0.19

ClinPred

0.019

GERP RS

2.7

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.055

gMVP

0.38

Mutation Taster

=94/6

polymorphism (auto)

(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