Genetic Variant EFHC2:p.Thr513Met (chrX-44232563-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

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

The NM_025184.4(EFHC2):c.1538C>T(p.Thr513Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000345 in 1,188,182 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T513T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000034 ( 0 hom. 10 hem. )

Consequence

EFHC2
NM_025184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.706

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12349045).

BS2

High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHC2	NM_025184.4 link	c.1538C>T	p.Thr513Met	missense_variant	Exon 10 of 15	ENST00000420999.2	NP_079460.2	Q5JST6-1
EFHC2	XM_047442535.1 link	c.1538C>T	p.Thr513Met	missense_variant	Exon 10 of 14		XP_047298491.1
EFHC2	XM_047442536.1 link	c.1538C>T	p.Thr513Met	missense_variant	Exon 10 of 15		XP_047298492.1
EFHC2	XM_006724562.3 link	c.950C>T	p.Thr317Met	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.1538C>T	p.Thr513Met	missense_variant	Exon 10 of 15	1	NM_025184.4	ENSP00000404232.2		Q5JST6-1

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

111950

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34126

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000618

AC:

AN:

145615

Hom.:

AF XY:

0.0000245

AC XY:

AN XY:

40855

show subpopulations

Gnomad AFR exome

AF:

0.0000987

Gnomad AMR exome

AF:

0.0000435

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:

0.0000952

Gnomad OTH exome

AF:

0.000266

GnomAD4 exome

AF:

0.0000344

AC:

AN:

1076180

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

347018

show subpopulations

Gnomad4 AFR exome

AF:

0.0000384

Gnomad4 AMR exome

AF:

0.0000307

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:

0.0000373

Gnomad4 OTH exome

AF:

0.0000883

GnomAD4 genome

AF:

0.0000357

AC:

AN:

112002

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34188

show subpopulations

Gnomad4 AFR

AF:

0.0000324

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:

0.0000564

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000153

AC:

ExAC

AF:

0.0000501

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1538C>T (p.T513M) alteration is located in exon 10 (coding exon 10) of the EFHC2 gene. This alteration results from a C to T substitution at nucleotide position 1538, causing the threonine (T) at amino acid position 513 to be replaced by a methionine (M). 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

0.093

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.6

DANN

Uncertain

0.98

DEOGEN2

Benign

0.025

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.74

M_CAP

Benign

0.020

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.27

REVEL

Benign

0.29

Sift4G

Benign

0.14

Polyphen

0.99

Vest4

0.24

MVP

0.30

MPC

0.36

ClinPred

0.13

GERP RS

-12

Varity_R

0.043

gMVP

0.56

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