X-44163957-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_025184.4(EFHC2):​c.2113G>A​(p.Val705Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 111,977 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

EFHC2
NM_025184.4 missense

Scores

15

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.53
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.027275175).
BP6
Variant X-44163957-C-T is Benign according to our data. Variant chrX-44163957-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3843661.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EFHC2NM_025184.4 linkc.2113G>A p.Val705Met missense_variant Exon 14 of 15 ENST00000420999.2 NP_079460.2 Q5JST6-1
EFHC2XM_047442535.1 linkc.2020G>A p.Val674Met missense_variant Exon 13 of 14 XP_047298491.1
EFHC2XM_006724562.3 linkc.1525G>A p.Val509Met missense_variant Exon 13 of 14 XP_006724625.1
EFHC2XM_047442536.1 linkc.*102G>A 3_prime_UTR_variant Exon 15 of 15 XP_047298492.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EFHC2ENST00000420999.2 linkc.2113G>A p.Val705Met missense_variant Exon 14 of 15 1 NM_025184.4 ENSP00000404232.2 Q5JST6-1
EFHC2ENST00000343571.3 linkn.434G>A non_coding_transcript_exon_variant Exon 4 of 5 2

Frequencies

GnomAD3 genomes
AF:
0.00000893
AC:
1
AN:
111977
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34147
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000948
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1056398
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
342674
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000893
AC:
1
AN:
111977
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34147
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000948
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Feb 05, 2025
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.84
CADD
Benign
0.0030
DANN
Benign
0.23
DEOGEN2
Benign
0.0053
T
FATHMM_MKL
Benign
0.0025
N
LIST_S2
Benign
0.57
T
M_CAP
Benign
0.0021
T
MetaRNN
Benign
0.027
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.55
N
PrimateAI
Benign
0.25
T
REVEL
Benign
0.073
Sift4G
Benign
0.44
T
Polyphen
0.085
B
Vest4
0.062
MutPred
0.38
Gain of ubiquitination at K702 (P = 0.056);
MVP
0.068
MPC
0.088
ClinPred
0.037
T
GERP RS
-8.2
Varity_R
0.059
gMVP
0.17

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: rs745886961; hg19: chrX-44023203; API