NM_025184.4:c.404G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_025184.4(EFHC2):c.404G>A(p.Arg135Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,189,572 control chromosomes in the GnomAD database, including 4 homozygotes. There are 618 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R135W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., 33 hem., cov: 22)

Exomes 𝑓: 0.0012 ( 4 hom. 585 hem. )

Consequence

EFHC2
NM_025184.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.63

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009518921).

BP6

Variant X-44261277-C-T is Benign according to our data. Variant chrX-44261277-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167032.

BS2

High Hemizygotes in GnomAd4 at 33 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
EFHC2	NM_025184.4 link	c.404G>A	p.Arg135Gln	missense_variant	Exon 4 of 15	ENST00000420999.2	NP_079460.2
EFHC2	XM_047442535.1 link	c.404G>A	p.Arg135Gln	missense_variant	Exon 4 of 14		XP_047298491.1
EFHC2	XM_047442536.1 link	c.404G>A	p.Arg135Gln	missense_variant	Exon 4 of 15		XP_047298492.1
EFHC2	XM_006724562.3 link	c.-185G>A		5_prime_UTR_variant	Exon 3 of 14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2 link	c.404G>A	p.Arg135Gln	missense_variant	Exon 4 of 15	1	NM_025184.4	ENSP00000404232.2

Frequencies

GnomAD3 genomes

AF:

0.000821

AC:

AN:

111998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000357

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000285

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0113

Gnomad FIN

AF:

0.000491

Gnomad MID

AF:

0.0125

Gnomad NFE

AF:

0.000752

Gnomad OTH

AF:

0.00134

GnomAD2 exomes

AF:

0.00214

AC:

362

AN:

168995

AF XY:

0.00270

show subpopulations

Gnomad AFR exome

AF:

0.0000830

Gnomad AMR exome

AF:

0.00227

Gnomad ASJ exome

AF:

0.000302

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000838

Gnomad NFE exome

AF:

0.000753

Gnomad OTH exome

AF:

0.00641

GnomAD4 exome

AF:

0.00120

AC:

1293

AN:

1077522

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

585

AN XY:

345996

show subpopulations

African (AFR)

AF:

0.000116

AC:

AN:

25925

American (AMR)

AF:

0.00222

AC:

AN:

33742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18667

East Asian (EAS)

AF:

0.0000335

AC:

AN:

29826

South Asian (SAS)

AF:

0.0136

AC:

680

AN:

50094

European-Finnish (FIN)

AF:

0.000449

AC:

AN:

40089

Middle Eastern (MID)

AF:

0.0138

AC:

AN:

3998

European-Non Finnish (NFE)

AF:

0.000467

AC:

388

AN:

830028

Other (OTH)

AF:

0.00162

AC:

AN:

45153

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000794

AC:

AN:

112050

Hom.:

Cov.:

AF XY:

0.000964

AC XY:

AN XY:

34226

show subpopulations

African (AFR)

AF:

0.000356

AC:

AN:

30905

American (AMR)

AF:

0.000284

AC:

AN:

10551

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.0106

AC:

AN:

2653

European-Finnish (FIN)

AF:

0.000491

AC:

AN:

6107

Middle Eastern (MID)

AF:

0.00913

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000752

AC:

AN:

53214

Other (OTH)

AF:

0.00132

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000893

Hom.:

Bravo

AF:

0.000665

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000781

AC:

ExAC

AF:

0.00282

AC:

341

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 20, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked intellectual disability

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The p.Arg135Gln variant in EFHC2 has been identified in at least 2 unrelated individuals with intellectual disability, segregated with disease in 2 families of unknown size (PMID: 17221867), and has been identified in >1% of South Asian chromosomes, 100 hemizygotes, and 1 homozygote by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for X-linked recessive mental retardation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.0061

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.042

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0095

MetaSVM

Benign

-0.28

MutationAssessor

Uncertain

2.6

PhyloP100

2.6

PrimateAI

Benign

0.37

REVEL

Uncertain

0.41

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.088

MVP

0.90

MPC

0.27

ClinPred

0.048

GERP RS

5.0

Varity_R

0.79

gMVP

0.79

Mutation Taster

=81/19

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over