chrX-44163957-C-T

Variant names:

• chrX-44163957-C-T
• rs745886961
• NM_025184.4:c.2113G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_025184.4(EFHC2):​c.2113G>A​(p.Val705Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 111,977 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: EFHC2 NM_025184.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.53
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027275175).
• BP6: Variant X-44163957-C-T is Benign according to our data. Variant chrX-44163957-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3843661.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2113G>A	p.Val705Met	missense	Exon 14 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.2113G>A	p.Val705Met	missense	Exon 14 of 15	ENSP00000404232.2	Q5JST6-1
	EFHC2	ENST00000937700.1		c.2020G>A	p.Val674Met	missense	Exon 13 of 14	ENSP00000607759.1
	EFHC2	ENST00000889038.1		c.1987G>A	p.Val663Met	missense	Exon 14 of 15	ENSP00000559097.1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111977 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000948

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1056398 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 342674

African (AFR) AF: 0.00 AC: 0 AN: 25259

American (AMR) AF: 0.00 AC: 0 AN: 30140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18654

East Asian (EAS) AF: 0.00 AC: 0 AN: 27931

South Asian (SAS) AF: 0.00 AC: 0 AN: 49053

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3523

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819749

Other (OTH) AF: 0.00 AC: 0 AN: 44349

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111977 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34147

African (AFR) AF: 0.00 AC: 0 AN: 30812

American (AMR) AF: 0.0000948 AC: 1 AN: 10549

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3585

South Asian (SAS) AF: 0.00 AC: 0 AN: 2709

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53200

Other (OTH) AF: 0.00 AC: 0 AN: 1522

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.076
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0030
DANN	Benign	0.23
DEOGEN2	Benign	0.0053	T
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-1.5
PrimateAI	Benign	0.25	T
REVEL	Benign	0.073
Sift4G	Benign	0.44	T
Polyphen		0.085	B
Vest4		0.062
MutPred		0.38		Gain of ubiquitination at K702 (P = 0.056)
MVP		0.068
MPC		0.088
ClinPred		0.037	T
GERP RS		-8.2
Varity_R		0.059
gMVP		0.17
Mutation Taster		=98/2	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: rs745886961; hg19: chrX-44023203;