Genetic Variant EFHC2:p.Gly271Asp (chrX-44250240-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_025184.4(EFHC2):c.812G>A(p.Gly271Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000082 in 1,097,454 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000082 ( 0 hom. 2 hem. )

Consequence

EFHC2
NM_025184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.30

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHC2	NM_025184.4 link	c.812G>A	p.Gly271Asp	missense_variant	Exon 5 of 15	ENST00000420999.2	NP_079460.2	Q5JST6-1
EFHC2	XM_047442535.1 link	c.812G>A	p.Gly271Asp	missense_variant	Exon 5 of 14		XP_047298491.1
EFHC2	XM_047442536.1 link	c.812G>A	p.Gly271Asp	missense_variant	Exon 5 of 15		XP_047298492.1
EFHC2	XM_006724562.3 link	c.224G>A	p.Gly75Asp	missense_variant	Exon 4 of 14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2 link	c.812G>A	p.Gly271Asp	missense_variant	Exon 5 of 15	1	NM_025184.4	ENSP00000404232.2		Q5JST6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1097454

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

362902

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26395

American (AMR)

AF:

0.00

AC:

AN:

35163

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19361

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.00

AC:

AN:

53981

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40429

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000107

AC:

AN:

841734

Other (OTH)

AF:

0.00

AC:

AN:

46059

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jan 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.812G>A (p.G271D) alteration is located in exon 5 (coding exon 5) of the EFHC2 gene. This alteration results from a G to A substitution at nucleotide position 812, causing the glycine (G) at amino acid position 271 to be replaced by an aspartic acid (D). 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

0.24

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

PhyloP100

5.3

PrimateAI

Uncertain

0.58

REVEL

Pathogenic

0.83

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.73

MutPred

0.86

Loss of MoRF binding (P = 0.053);

MVP

0.88

MPC

0.52

ClinPred

0.98

GERP RS

4.9

Varity_R

0.87

gMVP

0.91

Mutation Taster

=33/67

disease causing

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over