chr6-52452742-G-A

Variant names:

• chr6-52452742-G-A
• rs137852777
• NM_018100.4:c.628G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_018100.4(EFHC1):​c.628G>A​(p.Asp210Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 7.76

Genes affected

EFHC1 (HGNC:16406): (EF-hand domain containing 1) This gene encodes an EF-hand-containing calcium binding protein. The encoded protein likely plays a role in calcium homeostasis. Mutations in this gene have been associated with susceptibility to juvenile myoclonic epilepsy and juvenile absence epilepsy. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHC1	NM_018100.4	c.628G>A	p.Asp210Asn	missense_variant	Exon 4 of 11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2	c.571G>A	p.Asp191Asn	missense_variant	Exon 5 of 12		NP_001165891.1
EFHC1	NR_033327.2	n.697G>A		non_coding_transcript_exon_variant	Exon 4 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11	c.628G>A	p.Asp210Asn	missense_variant	Exon 4 of 11	1	NM_018100.4	ENSP00000360107.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251428 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000335

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Absence seizure;C1850778:Myoclonic epilepsy, juvenile, susceptibility to, 1 Uncertain:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 210 of the EFHC1 protein (p.Asp210Asn). This variant is present in population databases (rs137852777, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of juvenile myoclonic epilepsy (PMID: 15258581, 18823326, 22727576, 34645491). ClinVar contains an entry for this variant (Variation ID: 2065). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EFHC1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects EFHC1 function (PMID: 15258581, 22226147, 22926142). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Myoclonic epilepsy, juvenile, susceptibility to, 1 Other:1

Aug 01, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;.;.;D;T;T;T;T;T;.;T;.;T;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;.;D;D;D;D;D;D;D;D;.;.;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.7	.;.;.;H;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.8	.;.;.;D;.;.;.;.;.;.;.;.;.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0060	.;.;.;D;.;.;.;.;.;.;.;.;.;D
Sift4G	Uncertain	0.010	.;.;.;D;.;.;.;.;.;.;.;.;.;D
Polyphen		1.0	.;.;.;D;.;.;.;.;.;.;.;.;.;.
Vest4		0.95, 0.96
MutPred		0.91		.;.;.;Gain of catalytic residue at D210 (P = 0.05);Gain of catalytic residue at D210 (P = 0.05);Gain of catalytic residue at D210 (P = 0.05);Gain of catalytic residue at D210 (P = 0.05);Gain of catalytic residue at D210 (P = 0.05);.;Gain of catalytic residue at D210 (P = 0.05);.;.;.;.;
MVP		0.99
MPC		0.44
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.65
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137852777; hg19: chr6-52317540;