Variant X-44163941-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025184.4(EFHC2):c.2129C>T(p.Pro710Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000172 in 1,163,749 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: 9.5e-7 ( 0 hom. 0 hem. )

Consequence

EFHC2
NM_025184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.777

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:

EFHC2 (HGNC:):

EFHC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08970535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHC2	NM_025184.4 linkuse as main transcript	c.2129C>T	p.Pro710Leu	missense_variant	14/15	ENST00000420999.2	NP_079460.2	Q5JST6-1
EFHC2	XM_047442535.1 linkuse as main transcript	c.2036C>T	p.Pro679Leu	missense_variant	13/14		XP_047298491.1
EFHC2	XM_006724562.3 linkuse as main transcript	c.1541C>T	p.Pro514Leu	missense_variant	13/14		XP_006724625.1
EFHC2	XM_047442536.1 linkuse as main transcript	c.*118C>T		downstream_gene_variant			XP_047298492.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2 linkuse as main transcript	c.2129C>T	p.Pro710Leu	missense_variant	14/15	1	NM_025184.4	ENSP00000404232.2		Q5JST6-1
EFHC2	ENST00000343571.3 linkuse as main transcript	n.450C>T		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111848

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34044

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000658

GnomAD4 exome

AF:

9.51e-7

AC:

AN:

1051901

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

339905

show subpopulations

Gnomad4 AFR exome

AF:

0.0000399

Gnomad4 AMR exome

AF:

0.00

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:

0.00000894

AC:

AN:

111848

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34044

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.000658

Bravo

AF:

0.0000227

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

Jan 29, 2024

The c.2129C>T (p.P710L) alteration is located in exon 14 (coding exon 14) of the EFHC2 gene. This alteration results from a C to T substitution at nucleotide position 2129, causing the proline (P) at amino acid position 710 to be replaced by a leucine (L). 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

0.089

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.59

DEOGEN2

Benign

0.049

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.59

M_CAP

Benign

0.050

MetaRNN

Benign

0.090

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.26

REVEL

Benign

0.12

Sift4G

Benign

0.088

Polyphen

0.18

Vest4

0.055

MutPred

0.60

Loss of disorder (P = 0.0377);

MVP

0.14

MPC

0.085

ClinPred

0.13

GERP RS

3.3

Varity_R

0.049

gMVP

0.45

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