chrX-44232536-C-A

Variant names:

• chrX-44232536-C-A
• rs772087258
• NM_025184.4:c.1565G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025184.4(EFHC2):​c.1565G>T​(p.Arg522Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000169 in 1,181,309 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R522H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: EFHC2 NM_025184.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.195
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1565G>T	p.Arg522Leu	missense	Exon 10 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.1565G>T	p.Arg522Leu	missense	Exon 10 of 15	ENSP00000404232.2	Q5JST6-1
	EFHC2	ENST00000937700.1		c.1565G>T	p.Arg522Leu	missense	Exon 10 of 14	ENSP00000607759.1
	EFHC2	ENST00000889038.1		c.1439G>T	p.Arg480Leu	missense	Exon 10 of 15	ENSP00000559097.1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 112010 Hom.: 0 Cov.: 23

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000721 AC: 1 AN: 138782 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.35e-7 AC: 1 AN: 1069299 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 342839

African (AFR) AF: 0.00 AC: 0 AN: 25815

American (AMR) AF: 0.00 AC: 0 AN: 31664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18554

East Asian (EAS) AF: 0.00 AC: 0 AN: 29455

South Asian (SAS) AF: 0.00 AC: 0 AN: 48687

European-Finnish (FIN) AF: 0.0000255 AC: 1 AN: 39207

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4040

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 826907

Other (OTH) AF: 0.00 AC: 0 AN: 44970

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 112010 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34162

African (AFR) AF: 0.00 AC: 0 AN: 30788

American (AMR) AF: 0.00 AC: 0 AN: 10590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3594

South Asian (SAS) AF: 0.00 AC: 0 AN: 2672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6059

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53222

Other (OTH) AF: 0.00 AC: 0 AN: 1509

ExAC AF: 0.00000837 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.048
DANN	Benign	0.44
DEOGEN2	Benign	0.0014	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.26	N
PhyloP100		0.20
PrimateAI	Benign	0.21	T
REVEL	Benign	0.19
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.57		Loss of catalytic residue at R522 (P = 0.024)
MVP		0.13
MPC		0.10
ClinPred		0.079	T
GERP RS		-5.8
Varity_R		0.064
gMVP		0.49
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 26

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

Other links and lift over

dbSNP: rs772087258; hg19: chrX-44091782;