Genetic Variant EFHC2:p.Pro383Leu (chrX-44242253-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025184.4(EFHC2):c.1148C>T(p.Pro383Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,206,325 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000010 ( 0 hom. 1 hem. )

Consequence

EFHC2
NM_025184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.03

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHC2	NM_025184.4 link	c.1148C>T	p.Pro383Leu	missense_variant	Exon 8 of 15	ENST00000420999.2	NP_079460.2	Q5JST6-1
EFHC2	XM_047442535.1 link	c.1148C>T	p.Pro383Leu	missense_variant	Exon 8 of 14		XP_047298491.1
EFHC2	XM_047442536.1 link	c.1148C>T	p.Pro383Leu	missense_variant	Exon 8 of 15		XP_047298492.1
EFHC2	XM_006724562.3 link	c.560C>T	p.Pro187Leu	missense_variant	Exon 7 of 14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2 link	c.1148C>T	p.Pro383Leu	missense_variant	Exon 8 of 15	1	NM_025184.4	ENSP00000404232.2		Q5JST6-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111494

Hom.:

Cov.:

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:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000115

AC:

AN:

173959

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000256

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1094831

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360657

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

26326

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

34817

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19315

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

30129

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

53084

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40404

Gnomad4 NFE exome

AF:

0.0000119

AC:

AN:

840680

Gnomad4 Remaining exome

AF:

0.0000218

AC:

AN:

45956

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

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

AF:

0.0000179

AC:

AN:

111494

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33674

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000377

AC:

0.0000376662

AN:

0.0000376662

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1148C>T (p.P383L) alteration is located in exon 8 (coding exon 8) of the EFHC2 gene. This alteration results from a C to T substitution at nucleotide position 1148, causing the proline (P) at amino acid position 383 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

0.070

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.29

REVEL

Benign

0.082

Sift4G

Uncertain

0.055

Polyphen

0.38

Vest4

0.25

MutPred

0.29

Loss of glycosylation at P383 (P = 0.0113);

MVP

0.14

MPC

0.11

ClinPred

0.64

GERP RS

4.1

Varity_R

0.14

gMVP

0.72

Mutation Taster

=86/14

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.39

Position offset: -15

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