Variant X-44163981-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000420999.2(EFHC2):c.2089G>T(p.Ala697Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,162,905 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000010 ( 0 hom. 2 hem. )

Consequence

EFHC2
ENST00000420999.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.800

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25784093).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EFHC2	NM_025184.4 linkuse as main transcript	c.2089G>T	p.Ala697Ser	missense_variant	14/15	ENST00000420999.2	NP_079460.2
EFHC2	XM_047442535.1 linkuse as main transcript	c.1996G>T	p.Ala666Ser	missense_variant	13/14		XP_047298491.1
EFHC2	XM_006724562.3 linkuse as main transcript	c.1501G>T	p.Ala501Ser	missense_variant	13/14		XP_006724625.1
EFHC2	XM_047442536.1 linkuse as main transcript	c.*78G>T		3_prime_UTR_variant	15/15		XP_047298492.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2 linkuse as main transcript	c.2089G>T	p.Ala697Ser	missense_variant	14/15	1	NM_025184.4	ENSP00000404232	P1	Q5JST6-1
EFHC2	ENST00000343571.3 linkuse as main transcript	n.410G>T		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111739

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33939

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000951

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000662

AC:

AN:

120921

Hom.:

AF XY:

0.0000272

AC XY:

AN XY:

36745

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000389

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000105

AC:

AN:

1051166

Hom.:

Cov.:

AF XY:

0.00000592

AC XY:

AN XY:

338056

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000370

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111739

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33939

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000951

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000955

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2023

The c.2089G>T (p.A697S) alteration is located in exon 14 (coding exon 14) of the EFHC2 gene. This alteration results from a G to T substitution at nucleotide position 2089, causing the alanine (A) at amino acid position 697 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.058

DANN

Benign

0.50

DEOGEN2

Benign

0.0039

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.48

M_CAP

Benign

0.0031

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.27

REVEL

Benign

0.14

Sift4G

Benign

0.41

Polyphen

0.18

Vest4

0.10

MutPred

0.76

Gain of disorder (P = 0.0169);

MVP

0.13

MPC

0.077

ClinPred

0.036

GERP RS

0.25

Varity_R

0.064

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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