rs201560745

Variant names:

• chrX-44261277-C-T
• rs201560745
• NM_025184.4:c.404G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_025184.4(EFHC2):​c.404G>A​(p.Arg135Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,189,572 control chromosomes in the GnomAD database, including 4 homozygotes. There are 618 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R135W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., 33 hem., cov: 22)
  • Exomes 𝑓: 0.0012 (4 hom. 585 hem.)
• Consequence: EFHC2 NM_025184.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.63
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009518921).
• BP6: Variant X-44261277-C-T is Benign according to our data. Variant chrX-44261277-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167032.
• BS2: High Hemizygotes in GnomAd4 at 33 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.404G>A	p.Arg135Gln	missense	Exon 4 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.404G>A	p.Arg135Gln	missense	Exon 4 of 15	ENSP00000404232.2	Q5JST6-1
	EFHC2	ENST00000937700.1		c.404G>A	p.Arg135Gln	missense	Exon 4 of 14	ENSP00000607759.1
	EFHC2	ENST00000889038.1		c.278G>A	p.Arg93Gln	missense	Exon 4 of 15	ENSP00000559097.1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 92 AN: 111998 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000285

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0113

Gnomad FIN AF: 0.000491

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000752

Gnomad OTH AF: 0.00134

GnomAD2 exomes AF: 0.00214 AC: 362 AN: 168995 AF XY: 0.00270

Gnomad AFR exome AF: 0.0000830

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000838

Gnomad NFE exome AF: 0.000753

Gnomad OTH exome AF: 0.00641

GnomAD4 exome AF: 0.00120 AC: 1293 AN: 1077522 Hom.: 4 Cov.: 30 AF XY: 0.00169 AC XY: 585 AN XY: 345996

African (AFR) AF: 0.000116 AC: 3 AN: 25925

American (AMR) AF: 0.00222 AC: 75 AN: 33742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18667

East Asian (EAS) AF: 0.0000335 AC: 1 AN: 29826

South Asian (SAS) AF: 0.0136 AC: 680 AN: 50094

European-Finnish (FIN) AF: 0.000449 AC: 18 AN: 40089

Middle Eastern (MID) AF: 0.0138 AC: 55 AN: 3998

European-Non Finnish (NFE) AF: 0.000467 AC: 388 AN: 830028

Other (OTH) AF: 0.00162 AC: 73 AN: 45153

GnomAD4 genome AF: 0.000794 AC: 89 AN: 112050 Hom.: 0 Cov.: 22 AF XY: 0.000964 AC XY: 33 AN XY: 34226

African (AFR) AF: 0.000356 AC: 11 AN: 30905

American (AMR) AF: 0.000284 AC: 3 AN: 10551

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.0106 AC: 28 AN: 2653

European-Finnish (FIN) AF: 0.000491 AC: 3 AN: 6107

Middle Eastern (MID) AF: 0.00913 AC: 2 AN: 219

European-Non Finnish (NFE) AF: 0.000752 AC: 40 AN: 53214

Other (OTH) AF: 0.00132 AC: 2 AN: 1514

Alfa AF: 0.000893 Hom.: 28

Bravo AF: 0.000665

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000781 AC: 5

ExAC AF: 0.00282 AC: 341

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	X-linked intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0061	T
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.042	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.6
PrimateAI	Benign	0.37	T
REVEL	Uncertain	0.41
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.088
MVP		0.90
MPC		0.27
ClinPred		0.048	T
GERP RS		5.0
Varity_R		0.79
gMVP		0.79
Mutation Taster		=81/19	polymorphism (auto)

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: rs201560745; hg19: chrX-44120523; COSMIC: COSV101375455;