Variant X-44178470-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_025184.4(EFHC2):c.1846G>A(p.Asp616Asn) 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 1,206,443 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 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 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000011 ( 0 hom. 5 hem. )

Consequence

EFHC2
NM_025184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0270

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:

EFHC2 (HGNC:):

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=0.12982374).

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHC2	NM_025184.4 linkuse as main transcript	c.1846G>A	p.Asp616Asn	missense_variant	12/15	ENST00000420999.2	NP_079460.2	Q5JST6-1
EFHC2	XM_047442535.1 linkuse as main transcript	c.1846G>A	p.Asp616Asn	missense_variant	12/14		XP_047298491.1
EFHC2	XM_047442536.1 linkuse as main transcript	c.1846G>A	p.Asp616Asn	missense_variant	12/15		XP_047298492.1
EFHC2	XM_006724562.3 linkuse as main transcript	c.1258G>A	p.Asp420Asn	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.1846G>A	p.Asp616Asn	missense_variant	12/15	1	NM_025184.4	ENSP00000404232.2		Q5JST6-1
EFHC2	ENST00000343571.3 linkuse as main transcript	n.167G>A		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112509

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34665

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:

0.000371

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000174

AC:

AN:

172707

Hom.:

AF XY:

0.0000335

AC XY:

AN XY:

59685

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:

0.000178

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1093934

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

359836

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:

0.000189

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.00000889

AC:

AN:

112509

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34665

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:

0.000371

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000580

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

Mar 26, 2024

The c.1846G>A (p.D616N) alteration is located in exon 12 (coding exon 12) of the EFHC2 gene. This alteration results from a G to A substitution at nucleotide position 1846, causing the aspartic acid (D) at amino acid position 616 to be replaced by an asparagine (N). 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

0.084

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-1.0

CADD

Benign

2.9

DANN

Benign

0.96

DEOGEN2

Benign

0.0070

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.43

M_CAP

Benign

0.0035

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.26

REVEL

Benign

0.052

Sift4G

Benign

0.42

Polyphen

0.14

Vest4

0.037

MutPred

0.69

Gain of sheet (P = 0.1945);

MVP

0.11

MPC

0.085

ClinPred

0.013

GERP RS

0.51

Varity_R

0.059

gMVP

0.56

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