X-44232582-C-T

Variant names:

• chrX-44232582-C-T
• rs3747354
• NM_025184.4:c.1519G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_025184.4(EFHC2):​c.1519G>A​(p.Glu507Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000185 in 1,081,309 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. E507Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: EFHC2 NM_025184.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.33
• 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 -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• 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.1519G>A	p.Glu507Lys	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.1519G>A	p.Glu507Lys	missense	Exon 10 of 15	ENSP00000404232.2	Q5JST6-1
	EFHC2	ENST00000937700.1		c.1519G>A	p.Glu507Lys	missense	Exon 10 of 14	ENSP00000607759.1
	EFHC2	ENST00000889038.1		c.1393G>A	p.Glu465Lys	missense	Exon 10 of 15	ENSP00000559097.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1081309 Hom.: 0 Cov.: 29 AF XY: 0.00000569 AC XY: 2 AN XY: 351191

African (AFR) AF: 0.00 AC: 0 AN: 26153

American (AMR) AF: 0.00 AC: 0 AN: 33058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18967

East Asian (EAS) AF: 0.00 AC: 0 AN: 29726

South Asian (SAS) AF: 0.00 AC: 0 AN: 51162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39585

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4107

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 833049

Other (OTH) AF: 0.0000220 AC: 1 AN: 45502

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.3
PrimateAI	Benign	0.45	T
REVEL	Benign	0.28
Sift4G	Uncertain	0.0080	D
Polyphen		0.26	B
Vest4		0.34
MutPred		0.64		Gain of methylation at E507 (P = 0.0038)
MVP		0.34
MPC		0.14
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.89
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs3747354; hg19: chrX-44091828;