chrX-44261277-C-T

Position:

• chrX-44261277-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong 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).

• 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

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009518921).
• BS2: High Hemizygotes in GnomAd4 at 33 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHC2	NM_025184.4	c.404G>A	p.Arg135Gln	missense_variant	4/15	ENST00000420999.2	NP_079460.2
EFHC2	XM_047442535.1	c.404G>A	p.Arg135Gln	missense_variant	4/14		XP_047298491.1
EFHC2	XM_047442536.1	c.404G>A	p.Arg135Gln	missense_variant	4/15		XP_047298492.1
EFHC2	XM_006724562.3	c.-185G>A		5_prime_UTR_variant	3/14		XP_006724625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC2	ENST00000420999.2	c.404G>A	p.Arg135Gln	missense_variant	4/15	1	NM_025184.4	ENSP00000404232.2

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 92 AN: 111998 Hom.: 0 Cov.: 22 AF XY: 0.00102 AC XY: 35 AN XY: 34164

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

GnomAD3 exomes AF: 0.00214 AC: 362 AN: 168995 Hom.: 2 AF XY: 0.00270 AC XY: 152 AN XY: 56365

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 SAS exome AF: 0.0130

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

Gnomad4 AFR exome AF: 0.000116

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000335

Gnomad4 SAS exome AF: 0.0136

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.000467

Gnomad4 OTH exome AF: 0.00162

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

Gnomad4 AFR AF: 0.000356

Gnomad4 AMR AF: 0.000284

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.000491

Gnomad4 NFE AF: 0.000752

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.00101 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 20, 2013

- -

X-linked intellectual disability Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The p.Arg135Gln variant in EFHC2 has been identified in at least 2 unrelated individuals with intellectual disability, segregated with disease in 2 families of unknown size (PMID: 17221867), and has been identified in >1% of South Asian chromosomes, 100 hemizygotes, and 1 homozygote by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for X-linked recessive mental retardation. -

Computational scores

Source: dbNSFP v4.3

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
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

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