Genetic Variant EFHC2:p.Ile470Val (chrX-44235320-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_025184.4(EFHC2):c.1408A>G(p.Ile470Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,179,785 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 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. I470M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.00012 ( 0 hom. 38 hem. )

Consequence

EFHC2
NM_025184.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.409

Publications

2 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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026543736).

BP6

Variant X-44235320-T-C is Benign according to our data. Variant chrX-44235320-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2660364.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 6 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.1408A>G	p.Ile470Val	missense	Exon 9 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.1408A>G	p.Ile470Val	missense	Exon 9 of 15	ENSP00000404232.2	Q5JST6-1
EFHC2	ENST00000937700.1		c.1408A>G	p.Ile470Val	missense	Exon 9 of 14	ENSP00000607759.1
EFHC2	ENST00000889038.1		c.1282A>G	p.Ile428Val	missense	Exon 9 of 15	ENSP00000559097.1

Frequencies

GnomAD3 genomes

AF:

0.000161

AC:

AN:

111524

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00482

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000289

AC:

AN:

134847

AF XY:

0.000249

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00348

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000174

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

125

AN:

1068206

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

343994

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25843

American (AMR)

AF:

0.00

AC:

AN:

30864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18586

East Asian (EAS)

AF:

0.00337

AC:

AN:

29360

South Asian (SAS)

AF:

0.000284

AC:

AN:

49300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39013

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3967

European-Non Finnish (NFE)

AF:

0.00000484

AC:

AN:

826311

Other (OTH)

AF:

0.000178

AC:

AN:

44962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000152

AC:

AN:

111579

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

AN XY:

33771

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30691

American (AMR)

AF:

0.00

AC:

AN:

10546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00455

AC:

AN:

3514

South Asian (SAS)

AF:

0.00

AC:

AN:

2596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53074

Other (OTH)

AF:

0.00

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.534

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0000341

Hom.:

Bravo

AF:

0.000317

ExAC

AF:

0.000349

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.85

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.0013

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.62

M_CAP

Benign

0.0077

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

-0.41

PrimateAI

Benign

0.25

REVEL

Benign

0.017

Sift4G

Benign

0.96

Polyphen

0.0020

Vest4

0.0080

MVP

0.043

MPC

0.072

ClinPred

0.0073

GERP RS

-1.1

Varity_R

0.041

gMVP

0.45

Mutation Taster

=98/2

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