chr6-52454252-G-C

Variant names:

• chr6-52454252-G-C
• rs1570624
• NM_018100.4:c.881G>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.881G>C​(p.Arg294Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.04
• 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, 0.915

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHC1	NM_018100.4	MANE Select	c.881G>C	p.Arg294Pro	missense	Exon 5 of 11	NP_060570.2
	EFHC1	NM_001172420.2		c.824G>C	p.Arg275Pro	missense	Exon 6 of 12	NP_001165891.1
	EFHC1	NR_033327.2		n.2207G>C		non_coding_transcript_exon	Exon 4 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHC1	ENST00000371068.11	TSL:1 MANE Select	c.881G>C	p.Arg294Pro	missense	Exon 5 of 11	ENSP00000360107.4
	EFHC1	ENST00000637340.1	TSL:1	n.2806G>C		non_coding_transcript_exon	Exon 4 of 10
	EFHC1	ENST00000637353.1	TSL:5	c.881G>C	p.Arg294Pro	missense	Exon 5 of 11	ENSP00000490441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.70		Gain of loop (P = 0.0502)
MVP		0.96
MPC		0.56
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.93
Mutation Taster		=30/70	disease causing

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: rs1570624; hg19: chr6-52319050;