X-44232585-C-T

Position:

• chrX-44232585-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025184.4(EFHC2):​c.1516G>A​(p.Glu506Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 1,192,985 control chromosomes in the GnomAD database, including 15 homozygotes. There are 1,749 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (5 hom., 114 hem., cov: 23)
  • Exomes 𝑓: 0.0045 (10 hom. 1635 hem.)
• Consequence: EFHC2 NM_025184.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.68

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077182353).
• BP6: Variant X-44232585-C-T is Benign according to our data. Variant chrX-44232585-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1318353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-44232585-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00452 (4887/1080930) while in subpopulation MID AF= 0.0283 (116/4102). AF 95% confidence interval is 0.0241. There are 10 homozygotes in gnomad4_exome. There are 1635 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHC2	NM_025184.4	c.1516G>A	p.Glu506Lys	missense_variant	10/15	ENST00000420999.2	NP_079460.2
EFHC2	XM_047442535.1	c.1516G>A	p.Glu506Lys	missense_variant	10/14		XP_047298491.1
EFHC2	XM_047442536.1	c.1516G>A	p.Glu506Lys	missense_variant	10/15		XP_047298492.1
EFHC2	XM_006724562.3	c.928G>A	p.Glu310Lys	missense_variant	9/14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2	c.1516G>A	p.Glu506Lys	missense_variant	10/15	1	NM_025184.4	ENSP00000404232.2

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 371 AN: 112004 Hom.: 5 Cov.: 23 AF XY: 0.00337 AC XY: 115 AN XY: 34172

Gnomad AFR AF: 0.000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00208

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00413

Gnomad FIN AF: 0.00411

Gnomad MID AF: 0.0333

Gnomad NFE AF: 0.00479

Gnomad OTH AF: 0.00398

GnomAD3 exomes AF: 0.00412 AC: 618 AN: 149996 Hom.: 1 AF XY: 0.00438 AC XY: 195 AN XY: 44538

Gnomad AFR exome AF: 0.000489

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00772

Gnomad FIN exome AF: 0.00223

Gnomad NFE exome AF: 0.00503

Gnomad OTH exome AF: 0.00517

GnomAD4 exome AF: 0.00452 AC: 4887 AN: 1080930 Hom.: 10 Cov.: 29 AF XY: 0.00466 AC XY: 1635 AN XY: 350820

Gnomad4 AFR exome AF: 0.000344

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.0111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00723

Gnomad4 FIN exome AF: 0.00260

Gnomad4 NFE exome AF: 0.00451

Gnomad4 OTH exome AF: 0.00571

GnomAD4 genome AF: 0.00329 AC: 369 AN: 112055 Hom.: 5 Cov.: 23 AF XY: 0.00333 AC XY: 114 AN XY: 34233

Gnomad4 AFR AF: 0.000486

Gnomad4 AMR AF: 0.00207

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00376

Gnomad4 FIN AF: 0.00411

Gnomad4 NFE AF: 0.00479

Gnomad4 OTH AF: 0.00393

Alfa AF: 0.00514 Hom.: 68

Bravo AF: 0.00315

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00381 AC: 11

ESP6500AA AF: 0.000585 AC: 2

ESP6500EA AF: 0.00460 AC: 30

ExAC AF: 0.00377 AC: 452

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.37	T
REVEL	Benign	0.16
Sift4G	Benign	0.52	T
Polyphen		0.91	P
Vest4		0.12
MVP		0.36
MPC		0.15
ClinPred		0.015	T
GERP RS		5.0
Varity_R		0.34
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs192827775; hg19: chrX-44091831;