Variant X-44232527-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000420999.2(EFHC2):c.1574A>G(p.Asn525Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,179,077 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N525I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000037 ( 0 hom. 18 hem. )

Consequence

EFHC2
ENST00000420999.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040795565).

BS2

High Hemizygotes in GnomAdExome4 at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EFHC2	NM_025184.4 linkuse as main transcript	c.1574A>G	p.Asn525Ser	missense_variant	10/15	ENST00000420999.2	NP_079460.2
EFHC2	XM_047442535.1 linkuse as main transcript	c.1574A>G	p.Asn525Ser	missense_variant	10/14		XP_047298491.1
EFHC2	XM_047442536.1 linkuse as main transcript	c.1574A>G	p.Asn525Ser	missense_variant	10/15		XP_047298492.1
EFHC2	XM_006724562.3 linkuse as main transcript	c.986A>G	p.Asn329Ser	missense_variant	9/14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2 linkuse as main transcript	c.1574A>G	p.Asn525Ser	missense_variant	10/15	1	NM_025184.4	ENSP00000404232	P1	Q5JST6-1

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112129

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34285

show subpopulations

Gnomad AFR

AF:

0.0000974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000586

AC:

AN:

136577

Hom.:

AF XY:

0.0000289

AC XY:

AN XY:

34559

show subpopulations

Gnomad AFR exome

AF:

0.000202

Gnomad AMR exome

AF:

0.000139

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:

0.0000507

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000366

AC:

AN:

1066895

Hom.:

Cov.:

AF XY:

0.0000527

AC XY:

AN XY:

341371

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000223

Gnomad4 ASJ exome

AF:

0.0000542

Gnomad4 EAS exome

AF:

0.0000340

Gnomad4 SAS exome

AF:

0.0000206

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000291

Gnomad4 OTH exome

AF:

0.0000891

GnomAD4 genome

AF:

0.0000446

AC:

AN:

112182

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34348

show subpopulations

Gnomad4 AFR

AF:

0.0000972

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000375

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000292

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000840

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

Apr 22, 2022

The c.1574A>G (p.N525S) alteration is located in exon 10 (coding exon 10) of the EFHC2 gene. This alteration results from a A to G substitution at nucleotide position 1574, causing the asparagine (N) at amino acid position 525 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

0.079

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.6

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0097

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.74

M_CAP

Benign

0.0059

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.49

MutationTaster

Benign

0.57

PrimateAI

Benign

0.39

REVEL

Benign

0.071

Sift4G

Benign

0.091

Polyphen

0.0070

Vest4

0.057

MVP

0.12

MPC

0.071

ClinPred

0.022

GERP RS

2.2

Varity_R

0.091

gMVP

0.31

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