Variant rs201560745 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

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).

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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

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

BS2

High Hemizygotes in GnomAd4 at 33 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHC2	NM_025184.4 linkuse as main transcript	c.404G>A	p.Arg135Gln	missense_variant	4/15	ENST00000420999.2	NP_079460.2	Q5JST6-1
EFHC2	XM_047442535.1 linkuse as main transcript	c.404G>A	p.Arg135Gln	missense_variant	4/14		XP_047298491.1
EFHC2	XM_047442536.1 linkuse as main transcript	c.404G>A	p.Arg135Gln	missense_variant	4/15		XP_047298492.1
EFHC2	XM_006724562.3 linkuse as main transcript	c.-185G>A		5_prime_UTR_variant	3/14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2 linkuse as main transcript	c.404G>A	p.Arg135Gln	missense_variant	4/15	1	NM_025184.4	ENSP00000404232.2		Q5JST6-1

Frequencies

GnomAD3 genomes

AF:

0.000821

AC:

AN:

111998

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

34164

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

GnomAD3 exomes

AF:

0.00214

AC:

362

AN:

168995

Hom.:

AF XY:

0.00270

AC XY:

152

AN XY:

56365

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 SAS exome

AF:

0.0130

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

Gnomad4 AFR exome

AF:

0.000116

Gnomad4 AMR exome

AF:

0.00222

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000335

Gnomad4 SAS exome

AF:

0.0136

Gnomad4 FIN exome

AF:

0.000449

Gnomad4 NFE exome

AF:

0.000467

Gnomad4 OTH exome

AF:

0.00162

GnomAD4 genome

AF:

0.000794

AC:

AN:

112050

Hom.:

Cov.:

AF XY:

0.000964

AC XY:

AN XY:

34226

show subpopulations

Gnomad4 AFR

AF:

0.000356

Gnomad4 AMR

AF:

0.000284

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.000491

Gnomad4 NFE

AF:

0.000752

Gnomad4 OTH

AF:

0.00132

Alfa

AF:

0.00101

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

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 20, 2013

- -

X-linked intellectual disability

Benign:1

Benign, criteria provided, single submitter

research

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

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over