NM_025184.4:c.2089G>T

Variant names:

• chrX-44163981-C-A
• rs771911461
• NM_025184.4:c.2089G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_025184.4(EFHC2):​c.2089G>T​(p.Ala697Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,162,905 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 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: 0.000010 (0 hom. 2 hem.)
• Consequence: EFHC2 NM_025184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.800
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25784093).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025184.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHC2	NM_025184.4	MANE Select	c.2089G>T	p.Ala697Ser	missense	Exon 14 of 15	NP_079460.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHC2	ENST00000420999.2	TSL:1 MANE Select	c.2089G>T	p.Ala697Ser	missense	Exon 14 of 15	ENSP00000404232.2	Q5JST6-1
	EFHC2	ENST00000937700.1		c.1996G>T	p.Ala666Ser	missense	Exon 13 of 14	ENSP00000607759.1
	EFHC2	ENST00000889038.1		c.1963G>T	p.Ala655Ser	missense	Exon 14 of 15	ENSP00000559097.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111739 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000951

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

GnomAD2 exomes AF: 0.0000662 AC: 8 AN: 120921 AF XY: 0.0000272

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000389

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000105 AC: 11 AN: 1051166 Hom.: 0 Cov.: 27 AF XY: 0.00000592 AC XY: 2 AN XY: 338056

African (AFR) AF: 0.00 AC: 0 AN: 25115

American (AMR) AF: 0.000370 AC: 11 AN: 29706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18512

East Asian (EAS) AF: 0.00 AC: 0 AN: 27868

South Asian (SAS) AF: 0.00 AC: 0 AN: 47409

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3283

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 817502

Other (OTH) AF: 0.00 AC: 0 AN: 44137

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111739 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33939

African (AFR) AF: 0.00 AC: 0 AN: 30798

American (AMR) AF: 0.0000951 AC: 1 AN: 10511

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2673

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5959

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53147

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000955 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.058
DANN	Benign	0.50
DEOGEN2	Benign	0.0039	T
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.80
PrimateAI	Benign	0.27	T
REVEL	Benign	0.14
Sift4G	Benign	0.41	T
Polyphen		0.18	B
Vest4		0.10
MutPred		0.76		Gain of disorder (P = 0.0169)
MVP		0.13
MPC		0.077
ClinPred		0.036	T
GERP RS		0.25
Varity_R		0.064
gMVP		0.29
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771911461; hg19: chrX-44023227;