X-44242187-C-T

Variant summary

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

The ENST00000420999.2(EFHC2):​c.1214G>A​(p.Arg405His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,205,991 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

EFHC2
ENST00000420999.2 missense

Scores

1
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.74
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]

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=0.12419692).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EFHC2NM_025184.4 linkuse as main transcriptc.1214G>A p.Arg405His missense_variant 8/15 ENST00000420999.2 NP_079460.2
EFHC2XM_047442535.1 linkuse as main transcriptc.1214G>A p.Arg405His missense_variant 8/14 XP_047298491.1
EFHC2XM_047442536.1 linkuse as main transcriptc.1214G>A p.Arg405His missense_variant 8/15 XP_047298492.1
EFHC2XM_006724562.3 linkuse as main transcriptc.626G>A p.Arg209His missense_variant 7/14 XP_006724625.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EFHC2ENST00000420999.2 linkuse as main transcriptc.1214G>A p.Arg405His missense_variant 8/151 NM_025184.4 ENSP00000404232 P1Q5JST6-1

Frequencies

GnomAD3 genomes
AF:
0.0000269
AC:
3
AN:
111535
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
33735
show subpopulations
Gnomad AFR
AF:
0.0000652
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:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000578
AC:
1
AN:
173090
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
59774
show subpopulations
Gnomad AFR exome
AF:
0.0000837
Gnomad AMR exome
AF:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000548
AC:
6
AN:
1094456
Hom.:
0
Cov.:
30
AF XY:
0.00000278
AC XY:
1
AN XY:
360298
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000714
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000269
AC:
3
AN:
111535
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
33735
show subpopulations
Gnomad4 AFR
AF:
0.0000652
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:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.000314
AC:
1
ESP6500EA
AF:
0.00
AC:
0

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 submitterclinical testingAmbry GeneticsJun 17, 2024The c.1214G>A (p.R405H) alteration is located in exon 8 (coding exon 8) of the EFHC2 gene. This alteration results from a G to A substitution at nucleotide position 1214, causing the arginine (R) at amino acid position 405 to be replaced by a histidine (H). 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
0.13
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
12
DANN
Benign
0.37
DEOGEN2
Benign
0.0058
T
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.75
T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
1.9
L
MutationTaster
Benign
0.90
D
PrimateAI
Benign
0.24
T
REVEL
Benign
0.12
Sift4G
Benign
0.55
T
Polyphen
0.054
B
Vest4
0.30
MVP
0.53
MPC
0.11
ClinPred
0.053
T
GERP RS
5.0
Varity_R
0.058
gMVP
0.59

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.

Other links and lift over

dbSNP: rs376672087; hg19: chrX-44101433; API