X-44235318-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_025184.4(EFHC2):ā€‹c.1410A>Gā€‹(p.Ile470Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,178,143 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000090 ( 0 hom., 3 hem., cov: 23)
Exomes š‘“: 0.000084 ( 0 hom. 27 hem. )

Consequence

EFHC2
NM_025184.4 missense

Scores

1
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.167
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.059850305).
BS2
High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EFHC2NM_025184.4 linkuse as main transcriptc.1410A>G p.Ile470Met missense_variant 9/15 ENST00000420999.2 NP_079460.2 Q5JST6-1
EFHC2XM_047442535.1 linkuse as main transcriptc.1410A>G p.Ile470Met missense_variant 9/14 XP_047298491.1
EFHC2XM_047442536.1 linkuse as main transcriptc.1410A>G p.Ile470Met missense_variant 9/15 XP_047298492.1
EFHC2XM_006724562.3 linkuse as main transcriptc.822A>G p.Ile274Met missense_variant 8/14 XP_006724625.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EFHC2ENST00000420999.2 linkuse as main transcriptc.1410A>G p.Ile470Met missense_variant 9/151 NM_025184.4 ENSP00000404232.2 Q5JST6-1

Frequencies

GnomAD3 genomes
AF:
0.0000896
AC:
10
AN:
111569
Hom.:
0
Cov.:
23
AF XY:
0.0000889
AC XY:
3
AN XY:
33737
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:
0.000164
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000169
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000142
AC:
19
AN:
133764
Hom.:
0
AF XY:
0.0000560
AC XY:
2
AN XY:
35708
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000334
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000844
AC:
90
AN:
1066574
Hom.:
0
Cov.:
28
AF XY:
0.0000787
AC XY:
27
AN XY:
343028
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:
0.000109
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000896
AC:
10
AN:
111569
Hom.:
0
Cov.:
23
AF XY:
0.0000889
AC XY:
3
AN XY:
33737
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000164
Gnomad4 NFE
AF:
0.000169
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000218
Hom.:
2
Bravo
AF:
0.000106
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000471
AC:
3
ExAC
AF:
0.000145
AC:
17

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 GeneticsMay 30, 2023The c.1410A>G (p.I470M) alteration is located in exon 9 (coding exon 9) of the EFHC2 gene. This alteration results from a A to G substitution at nucleotide position 1410, causing the isoleucine (I) at amino acid position 470 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
0.10
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
16
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0060
T
FATHMM_MKL
Benign
0.63
D
LIST_S2
Benign
0.65
T
M_CAP
Benign
0.0082
T
MetaRNN
Benign
0.060
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
L
PrimateAI
Benign
0.25
T
REVEL
Benign
0.048
Sift4G
Benign
0.19
T
Polyphen
0.92
P
Vest4
0.066
MVP
0.19
MPC
0.12
ClinPred
0.087
T
GERP RS
1.6
Varity_R
0.13
gMVP
0.54

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: rs368484783; hg19: chrX-44094564; API