Genetic Variant EFHC2:p.Glu507Gln (chrX-44232582-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025184.4(EFHC2):c.1519G>C(p.Glu507Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00509 in 1,193,311 control chromosomes in the GnomAD database, including 127 homozygotes. There are 1,864 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0064 ( 7 hom., 260 hem., cov: 23)

Exomes 𝑓: 0.0050 ( 120 hom. 1604 hem. )

Consequence

EFHC2
NM_025184.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.33

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062425435).

BP6

Variant X-44232582-C-G is Benign according to our data. Variant chrX-44232582-C-G is described in ClinVar as [Benign]. Clinvar id is 193745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHC2	NM_025184.4 link	c.1519G>C	p.Glu507Gln	missense_variant	Exon 10 of 15	ENST00000420999.2	NP_079460.2	Q5JST6-1
EFHC2	XM_047442535.1 link	c.1519G>C	p.Glu507Gln	missense_variant	Exon 10 of 14		XP_047298491.1
EFHC2	XM_047442536.1 link	c.1519G>C	p.Glu507Gln	missense_variant	Exon 10 of 15		XP_047298492.1
EFHC2	XM_006724562.3 link	c.931G>C	p.Glu311Gln	missense_variant	Exon 9 of 14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2 link	c.1519G>C	p.Glu507Gln	missense_variant	Exon 10 of 15	1	NM_025184.4	ENSP00000404232.2		Q5JST6-1

Frequencies

GnomAD3 genomes

AF:

0.00640

AC:

717

AN:

111967

Hom.:

Cov.:

AF XY:

0.00756

AC XY:

258

AN XY:

34135

show subpopulations

Gnomad AFR

AF:

0.00143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0248

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0745

Gnomad SAS

AF:

0.00225

Gnomad FIN

AF:

0.00923

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.00667

GnomAD3 exomes

AF:

0.0128

AC:

1922

AN:

150593

Hom.:

AF XY:

0.0104

AC XY:

468

AN XY:

44901

show subpopulations

Gnomad AFR exome

AF:

0.00137

Gnomad AMR exome

AF:

0.0321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0770

Gnomad SAS exome

AF:

0.00146

Gnomad FIN exome

AF:

0.00760

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.00872

GnomAD4 exome

AF:

0.00495

AC:

5357

AN:

1081291

Hom.:

120

Cov.:

AF XY:

0.00457

AC XY:

1604

AN XY:

351183

show subpopulations

Gnomad4 AFR exome

AF:

0.000841

Gnomad4 AMR exome

AF:

0.0346

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0888

Gnomad4 SAS exome

AF:

0.00156

Gnomad4 FIN exome

AF:

0.00680

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.00604

GnomAD4 genome

AF:

0.00643

AC:

720

AN:

112020

Hom.:

Cov.:

AF XY:

0.00760

AC XY:

260

AN XY:

34198

show subpopulations

Gnomad4 AFR

AF:

0.00143

Gnomad4 AMR

AF:

0.0250

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0747

Gnomad4 SAS

AF:

0.00226

Gnomad4 FIN

AF:

0.00923

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.00658

Alfa

AF:

0.00372

Hom.:

Bravo

AF:

0.00815

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00138

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00138

AC:

ExAC

AF:

0.00947

AC:

1134

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 20, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0062

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.0

PrimateAI

Benign

0.41

REVEL

Benign

0.20

Sift4G

Uncertain

0.010

Polyphen

0.26

Vest4

0.11

MPC

0.19

ClinPred

0.0098

GERP RS

5.8

Varity_R

0.29

gMVP

0.84

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