Variant X-44178494-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000420999.2(EFHC2):c.1822C>T(p.Arg608Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,092,492 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R608H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000033 ( 0 hom. 7 hem. )

Consequence

EFHC2
ENST00000420999.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.610

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22353408).

BS2

High Hemizygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EFHC2	NM_025184.4 linkuse as main transcript	c.1822C>T	p.Arg608Cys	missense_variant	12/15	ENST00000420999.2	NP_079460.2
EFHC2	XM_047442535.1 linkuse as main transcript	c.1822C>T	p.Arg608Cys	missense_variant	12/14		XP_047298491.1
EFHC2	XM_047442536.1 linkuse as main transcript	c.1822C>T	p.Arg608Cys	missense_variant	12/15		XP_047298492.1
EFHC2	XM_006724562.3 linkuse as main transcript	c.1234C>T	p.Arg412Cys	missense_variant	11/14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2 linkuse as main transcript	c.1822C>T	p.Arg608Cys	missense_variant	12/15	1	NM_025184.4	ENSP00000404232	P1	Q5JST6-1
EFHC2	ENST00000343571.3 linkuse as main transcript	n.143C>T		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000347

AC:

AN:

172945

Hom.:

AF XY:

0.0000335

AC XY:

AN XY:

59783

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:

0.0000767

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000330

AC:

AN:

1092492

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

358392

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000393

Gnomad4 OTH exome

AF:

0.0000436

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000414

AC:

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 submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.1822C>T (p.R608C) alteration is located in exon 12 (coding exon 12) of the EFHC2 gene. This alteration results from a C to T substitution at nucleotide position 1822, causing the arginine (R) at amino acid position 608 to be replaced by a cysteine (C). 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

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.24

REVEL

Uncertain

0.31

Sift4G

Benign

0.082

Polyphen

1.0

Vest4

0.22

MutPred

0.55

Loss of solvent accessibility (P = 0.0404);

MVP

0.23

MPC

0.41

ClinPred

0.42

GERP RS

0.38

Varity_R

0.14

gMVP

0.33

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.

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