Genetic Variant EFHC2:p.Arg608His (chrX-44178493-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_025184.4(EFHC2):c.1823G>A(p.Arg608His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000914 in 1,204,024 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R608L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000064 ( 0 hom. 2 hem. )

Consequence

EFHC2
NM_025184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.337

Publications

0 publications found

Variant links:

Genes affected

EFHC2 (HGNC:26233): (EF-hand domain containing 2) This gene encodes a protein which contains three DM10 domains and three calcium-binding EF-hand motifs. A related protein is encoded by a gene on chromosome 6. It has been suggested that both proteins are involved in the development of epilepsy (PMID: 15258581, 16112844) and that this gene may be associated with fear recognition in individuals with Turner syndrome. [provided by RefSeq, Aug 2011]

EFHC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1369735).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025184.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHC2	NM_025184.4	MANE Select	c.1823G>A	p.Arg608His	missense	Exon 12 of 15	NP_079460.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFHC2	ENST00000420999.2	TSL:1 MANE Select	c.1823G>A	p.Arg608His	missense	Exon 12 of 15	ENSP00000404232.2	Q5JST6-1
EFHC2	ENST00000937700.1		c.1823G>A	p.Arg608His	missense	Exon 12 of 14	ENSP00000607759.1
EFHC2	ENST00000889038.1		c.1697G>A	p.Arg566His	missense	Exon 12 of 15	ENSP00000559097.1

Frequencies

GnomAD3 genomes

AF:

0.0000355

AC:

AN:

112540

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000646

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000937

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000187

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000174

AC:

AN:

172828

AF XY:

0.0000168

show subpopulations

Gnomad AFR exome

AF:

0.000171

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000759

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000641

AC:

AN:

1091484

Hom.:

Cov.:

AF XY:

0.00000560

AC XY:

AN XY:

357444

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26282

American (AMR)

AF:

0.00

AC:

AN:

34514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19206

East Asian (EAS)

AF:

0.0000664

AC:

AN:

30111

South Asian (SAS)

AF:

0.00

AC:

AN:

51937

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40429

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4123

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

838981

Other (OTH)

AF:

0.00

AC:

AN:

45901

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000355

AC:

AN:

112540

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34706

show subpopulations

African (AFR)

AF:

0.0000646

AC:

AN:

30955

American (AMR)

AF:

0.0000937

AC:

AN:

10677

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3609

South Asian (SAS)

AF:

0.00

AC:

AN:

2700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6159

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000187

AC:

AN:

53352

Other (OTH)

AF:

0.00

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.1

PhyloP100

0.34

PrimateAI

Benign

0.22

REVEL

Benign

0.21

Sift4G

Benign

0.23

Polyphen

0.99

Vest4

0.071

MutPred

0.39

Loss of solvent accessibility (P = 0.0635)

MVP

0.26

MPC

0.32

ClinPred

0.13

GERP RS

2.7

Varity_R

0.055

gMVP

0.22

Mutation Taster

=100/0

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