rs376768756

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-44232527-T-A
• chrX-44232527-T-C

Variant summary

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

The NM_025184.4(EFHC2):​c.1574A>T​(p.Asn525Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000937 in 1,066,898 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. N525S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 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: 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.1574A>T	p.Asn525Ile	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>T	p.Asn525Ile	missense	Exon 10 of 15	ENSP00000404232.2	Q5JST6-1
	EFHC2	ENST00000937700.1		c.1574A>T	p.Asn525Ile	missense	Exon 10 of 14	ENSP00000607759.1
	EFHC2	ENST00000889038.1		c.1448A>T	p.Asn483Ile	missense	Exon 10 of 15	ENSP00000559097.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.37e-7 AC: 1 AN: 1066898 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 341374

African (AFR) AF: 0.00 AC: 0 AN: 25758

American (AMR) AF: 0.00 AC: 0 AN: 31393

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18452

East Asian (EAS) AF: 0.00 AC: 0 AN: 29395

South Asian (SAS) AF: 0.00 AC: 0 AN: 48434

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4029

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 825450

Other (OTH) AF: 0.00 AC: 0 AN: 44891

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	0.0042	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.8
PrimateAI	Benign	0.43	T
REVEL	Uncertain	0.43
Sift4G	Uncertain	0.0030	D
Polyphen		0.90	P
Vest4		0.56
MutPred		0.68		Gain of sheet (P = 0.0827)
MVP		0.34
MPC		0.33
ClinPred		0.97	D
GERP RS		2.2
Varity_R		0.68
gMVP		0.60
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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;