rs1554258778

Variant names:

• chr6-52438397-G-C
• rs1554258778
• NM_018100.4:c.379G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-52438397-G-C
• chr6-52438397-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018100.4(EFHC1):​c.379G>C​(p.Glu127Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

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]

EFHC1 Gene-Disease associations (from GenCC):

• juvenile myoclonic epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHC1	NM_018100.4	c.379G>C	p.Glu127Gln	missense_variant	Exon 3 of 11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2	c.322G>C	p.Glu108Gln	missense_variant	Exon 4 of 12		NP_001165891.1
EFHC1	NR_033327.2	n.448G>C		non_coding_transcript_exon_variant	Exon 3 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11	c.379G>C	p.Glu127Gln	missense_variant	Exon 3 of 11	1	NM_018100.4	ENSP00000360107.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 18, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with glutamine at codon 127 of the EFHC1 protein (p.Glu127Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with EFHC1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.;.;T;T;T;T;T;T;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D;D;.;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.0	.;.;.;.;H;.;.;.;.;.;.;.;.;.
PhyloP100		10
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.0	.;.;.;.;D;.;.;.;.;.;.;.;.;D
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.;D;.;.;.;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	.;.;.;.;D;.;.;.;.;.;.;.;.;D
Vest4		0.0
ClinPred		1.0	D
GERP RS		5.8
PromoterAI		-0.013	Neutral
Varity_R		0.50
gMVP		0.70
Mutation Taster		=56/44	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: rs1554258778; hg19: chr6-52303195;