rs1266787

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.1343T>C(p.Met448Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,614,020 control chromosomes in the GnomAD database, including 2,319 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. M448R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.075 ( 883 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1436 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.69

Publications

21 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=0.001758635).

BP6

Variant 6-52479101-T-C is Benign according to our data. Variant chr6-52479101-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 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.1343T>C	p.Met448Thr	missense	Exon 8 of 11	NP_060570.2	Q5JVL4-1
EFHC1	NM_001172420.2		c.1286T>C	p.Met429Thr	missense	Exon 9 of 12	NP_001165891.1	Q5JVL4-3
EFHC1	NR_033327.2		n.2669T>C		non_coding_transcript_exon	Exon 7 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFHC1	ENST00000371068.11	TSL:1 MANE Select	c.1343T>C	p.Met448Thr	missense	Exon 8 of 11	ENSP00000360107.4	Q5JVL4-1
EFHC1	ENST00000637340.1	TSL:1	n.3268T>C		non_coding_transcript_exon	Exon 7 of 10
EFHC1	ENST00000637353.1	TSL:5	c.1343T>C	p.Met448Thr	missense	Exon 8 of 11	ENSP00000490441.1	A0A1B0GVB0

Frequencies

GnomAD3 genomes

AF:

0.0747

AC:

11366

AN:

152086

Hom.:

881

Cov.:

show subpopulations

Gnomad AFR

AF:

0.193

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0427

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0120

Gnomad FIN

AF:

0.0222

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0325

Gnomad OTH

AF:

0.0607

GnomAD2 exomes

AF:

0.0355

AC:

8920

AN:

251346

AF XY:

0.0316

show subpopulations

Gnomad AFR exome

AF:

0.198

Gnomad AMR exome

AF:

0.0254

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0212

Gnomad NFE exome

AF:

0.0327

Gnomad OTH exome

AF:

0.0290

GnomAD4 exome

AF:

0.0339

AC:

49496

AN:

1461816

Hom.:

1436

Cov.:

AF XY:

0.0326

AC XY:

23715

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.201

AC:

6725

AN:

33470

American (AMR)

AF:

0.0274

AC:

1226

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

326

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0111

AC:

954

AN:

86256

European-Finnish (FIN)

AF:

0.0224

AC:

1196

AN:

53418

Middle Eastern (MID)

AF:

0.0507

AC:

292

AN:

5758

European-Non Finnish (NFE)

AF:

0.0327

AC:

36332

AN:

1111968

Other (OTH)

AF:

0.0405

AC:

2443

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2805

5609

8414

11218

14023

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1404

2808

4212

5616

7020

<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:

0.0748

AC:

11384

AN:

152204

Hom.:

883

Cov.:

AF XY:

0.0728

AC XY:

5420

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.193

AC:

8022

AN:

41504

American (AMR)

AF:

0.0426

AC:

652

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.0118

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0222

AC:

235

AN:

10608

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0325

AC:

2209

AN:

68004

Other (OTH)

AF:

0.0605

AC:

128

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

494

989

1483

1978

2472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0448

Hom.:

1307

Bravo

AF:

0.0820

TwinsUK

AF:

0.0380

AC:

141

ALSPAC

AF:

0.0298

AC:

115

ESP6500AA

AF:

0.196

AC:

864

ESP6500EA

AF:

0.0298

AC:

256

ExAC

AF:

0.0389

AC:

4728

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0364

EpiControl

AF:

0.0359

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Juvenile myoclonic epilepsy (2)

not provided (2)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.059

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.63

PhyloP100

2.7

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.9

REVEL

Benign

0.050

Sift

Benign

0.63

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.20

MPC

0.11

ClinPred

0.0097

GERP RS

3.6

Varity_R

0.17

gMVP

0.52

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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