X-44235338-T-A

Position:

• chrX-44235338-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000420999.2(EFHC2):​c.1390A>T​(p.Ile464Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: EFHC2 ENST00000420999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.376

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHC2	NM_025184.4	c.1390A>T	p.Ile464Phe	missense_variant	9/15	ENST00000420999.2	NP_079460.2
EFHC2	XM_047442535.1	c.1390A>T	p.Ile464Phe	missense_variant	9/14		XP_047298491.1
EFHC2	XM_047442536.1	c.1390A>T	p.Ile464Phe	missense_variant	9/15		XP_047298492.1
EFHC2	XM_006724562.3	c.802A>T	p.Ile268Phe	missense_variant	8/14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2	c.1390A>T	p.Ile464Phe	missense_variant	9/15	1	NM_025184.4	ENSP00000404232	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2024

The c.1390A>T (p.I464F) alteration is located in exon 9 (coding exon 9) of the EFHC2 gene. This alteration results from a A to T substitution at nucleotide position 1390, causing the isoleucine (I) at amino acid position 464 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	8.3
DANN	Benign	0.95
DEOGEN2	Benign	0.032	T
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
REVEL	Uncertain	0.30
Sift4G	Uncertain	0.058	T
Polyphen		0.49	P
Vest4		0.63
MutPred		0.57		Loss of sheet (P = 0.1501);
MVP		0.52
MPC		0.30
ClinPred		0.33	T
GERP RS		-0.079
Varity_R		0.27
gMVP		0.90

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-44094584;