NM_018100.4:c.379G>C

Variant names:

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018100.4. 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
	EFHC1	NM_018100.4	MANE Select	c.379G>C	p.Glu127Gln	missense	Exon 3 of 11	NP_060570.2	Q5JVL4-1
	EFHC1	NM_001172420.2		c.322G>C	p.Glu108Gln	missense	Exon 4 of 12	NP_001165891.1	Q5JVL4-3
	EFHC1	NR_033327.2		n.448G>C		non_coding_transcript_exon	Exon 3 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHC1	ENST00000371068.11	TSL:1 MANE Select	c.379G>C	p.Glu127Gln	missense	Exon 3 of 11	ENSP00000360107.4	Q5JVL4-1
	EFHC1	ENST00000637340.1	TSL:1	n.1047G>C		non_coding_transcript_exon	Exon 3 of 10
	EFHC1	ENST00000637353.1	TSL:5	c.379G>C	p.Glu127Gln	missense	Exon 3 of 11	ENSP00000490441.1	A0A1B0GVB0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Absence seizure;C1850778:Myoclonic epilepsy, juvenile, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		10
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.81		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.90
MPC		0.47
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;