6-52454258-G-T

Variant names:

• chr6-52454258-G-T
• rs115205076
• NM_018100.4:c.887G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018100.4(EFHC1):​c.887G>T​(p.Arg296Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,128 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R296H) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHC1	NM_018100.4	c.887G>T	p.Arg296Leu	missense_variant	Exon 5 of 11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2	c.830G>T	p.Arg277Leu	missense_variant	Exon 6 of 12		NP_001165891.1
EFHC1	NR_033327.2	n.2213G>T		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.887G>T	p.Arg296Leu	missense_variant	Exon 5 of 11	1	NM_018100.4	ENSP00000360107.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74298

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.;T;T;T;T;T;T;.;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.0	.;.;.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.2	.;.;.;D;.;.;.;.;.;.;.;.;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	.;.;.;D;.;.;.;.;.;.;.;.;D
Sift4G	Uncertain	0.013	.;.;.;D;.;.;.;.;.;.;.;.;D
Polyphen		0.29	.;.;.;B;.;.;.;.;.;.;.;.;.
Vest4		0.67, 0.68
MutPred		0.67		.;.;.;Loss of methylation at R296 (P = 0.0362);Loss of methylation at R296 (P = 0.0362);Loss of methylation at R296 (P = 0.0362);Loss of methylation at R296 (P = 0.0362);Loss of methylation at R296 (P = 0.0362);.;Loss of methylation at R296 (P = 0.0362);.;.;.;
MVP		0.78
MPC		0.33
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.58
gMVP		0.71

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: rs115205076; hg19: chr6-52319056;