X-44232527-T-C

Variant names:

• chrX-44232527-T-C
• rs376768756
• NM_025184.4:c.1574A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_025184.4(EFHC2):​c.1574A>G​(p.Asn525Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,179,077 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. N525I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000037 (0 hom. 18 hem.)
• Consequence: EFHC2 NM_025184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040795565).
• BS2: High Hemizygotes in GnomAdExome4 at 18 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.1574A>G	p.Asn525Ser	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.1574A>G	p.Asn525Ser	missense	Exon 10 of 15	ENSP00000404232.2	Q5JST6-1
	EFHC2	ENST00000937700.1		c.1574A>G	p.Asn525Ser	missense	Exon 10 of 14	ENSP00000607759.1
	EFHC2	ENST00000889038.1		c.1448A>G	p.Asn483Ser	missense	Exon 10 of 15	ENSP00000559097.1

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112129 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000586 AC: 8 AN: 136577 AF XY: 0.0000289

Gnomad AFR exome AF: 0.000202

Gnomad AMR exome AF: 0.000139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000507

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000366 AC: 39 AN: 1066895 Hom.: 0 Cov.: 29 AF XY: 0.0000527 AC XY: 18 AN XY: 341371

African (AFR) AF: 0.00 AC: 0 AN: 25757

American (AMR) AF: 0.000223 AC: 7 AN: 31393

Ashkenazi Jewish (ASJ) AF: 0.0000542 AC: 1 AN: 18452

East Asian (EAS) AF: 0.0000340 AC: 1 AN: 29395

South Asian (SAS) AF: 0.0000206 AC: 1 AN: 48435

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39096

Middle Eastern (MID) AF: 0.000248 AC: 1 AN: 4029

European-Non Finnish (NFE) AF: 0.0000291 AC: 24 AN: 825447

Other (OTH) AF: 0.0000891 AC: 4 AN: 44891

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112182 Hom.: 0 Cov.: 23 AF XY: 0.0000291 AC XY: 1 AN XY: 34348

African (AFR) AF: 0.0000972 AC: 3 AN: 30876

American (AMR) AF: 0.00 AC: 0 AN: 10616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3589

South Asian (SAS) AF: 0.000375 AC: 1 AN: 2669

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53228

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000292 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000840 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	0.079
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0097	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.49	N
PhyloP100		1.8
PrimateAI	Benign	0.39	T
REVEL	Benign	0.071
Sift4G	Benign	0.091	T
Polyphen		0.0070	B
Vest4		0.057
MVP		0.12
MPC		0.071
ClinPred		0.022	T
GERP RS		2.2
Varity_R		0.091
gMVP		0.31
Mutation Taster		=97/3	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: rs376768756; hg19: chrX-44091773;