Genetic Variant EFHC2:p.Asp742Glu (chrX-44148819-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025184.4(EFHC2):c.2226C>A(p.Asp742Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

EFHC2
NM_025184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.06

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08260822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
EFHC2	NM_025184.4 link	c.2226C>A	p.Asp742Glu	missense_variant	Exon 15 of 15	ENST00000420999.2	NP_079460.2
EFHC2	XM_047442535.1 link	c.2133C>A	p.Asp711Glu	missense_variant	Exon 14 of 14		XP_047298491.1
EFHC2	XM_006724562.3 link	c.1638C>A	p.Asp546Glu	missense_variant	Exon 14 of 14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2 link	c.2226C>A	p.Asp742Glu	missense_variant	Exon 15 of 15	1	NM_025184.4	ENSP00000404232.2
EFHC2	ENST00000343571.3 link	n.547C>A		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1070563

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

347381

African (AFR)

AF:

0.00

AC:

AN:

25797

American (AMR)

AF:

0.00

AC:

AN:

31257

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18819

East Asian (EAS)

AF:

0.00

AC:

AN:

28955

South Asian (SAS)

AF:

0.00

AC:

AN:

50070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38987

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4104

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

827456

Other (OTH)

AF:

0.00

AC:

AN:

45118

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2226C>A (p.D742E) alteration is located in exon 15 (coding exon 15) of the EFHC2 gene. This alteration results from a C to A substitution at nucleotide position 2226, causing the aspartic acid (D) at amino acid position 742 to be replaced by a glutamic acid (E). 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

0.20

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0010

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.015

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.39

M_CAP

Benign

0.0041

MetaRNN

Benign

0.083

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

-1.1

PrimateAI

Benign

0.48

REVEL

Benign

0.15

Sift4G

Benign

0.24

Polyphen

0.14

Vest4

0.31

MutPred

0.41

Gain of methylation at K741 (P = 0.0762);

MVP

0.24

MPC

0.14

ClinPred

0.13

GERP RS

-11

Varity_R

0.15

gMVP

0.47

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over