X-44235338-T-C

Variant names:

• chrX-44235338-T-C
• NM_025184.4:c.1390A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025184.4(EFHC2):​c.1390A>G​(p.Ile464Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,075,434 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: EFHC2 NM_025184.4 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.081977844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHC2	NM_025184.4	c.1390A>G	p.Ile464Val	missense_variant	Exon 9 of 15	ENST00000420999.2	NP_079460.2
EFHC2	XM_047442535.1	c.1390A>G	p.Ile464Val	missense_variant	Exon 9 of 14		XP_047298491.1
EFHC2	XM_047442536.1	c.1390A>G	p.Ile464Val	missense_variant	Exon 9 of 15		XP_047298492.1
EFHC2	XM_006724562.3	c.802A>G	p.Ile268Val	missense_variant	Exon 8 of 14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2	c.1390A>G	p.Ile464Val	missense_variant	Exon 9 of 15	1	NM_025184.4	ENSP00000404232.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1075434 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 348554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000241

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1390A>G (p.I464V) alteration is located in exon 9 (coding exon 9) of the EFHC2 gene. This alteration results from a A to G substitution at nucleotide position 1390, causing the isoleucine (I) at amino acid position 464 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.49
DANN	Benign	0.77
DEOGEN2	Benign	0.0072	T
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.28	T
REVEL	Benign	0.073
Sift4G	Benign	0.14	T
Polyphen		0.15	B
Vest4		0.087
MutPred		0.54		Loss of loop (P = 0.2237);
MVP		0.19
MPC		0.082
ClinPred		0.14	T
GERP RS		-0.079
Varity_R		0.12
gMVP		0.55

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;