rs796052414

Variant names:

• chr6-52454197-C-G
• rs796052414
• NM_018100.4:c.826C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-52454197-C-G
• chr6-52454197-C-T

Variant summary

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

The NM_018100.4(EFHC1):​c.826C>G​(p.Arg276Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 1.02

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.826C>G	p.Arg276Gly	missense_variant	Exon 5 of 11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2	c.769C>G	p.Arg257Gly	missense_variant	Exon 6 of 12		NP_001165891.1
EFHC1	NR_033327.2	n.2152C>G		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.826C>G	p.Arg276Gly	missense_variant	Exon 5 of 11	1	NM_018100.4	ENSP00000360107.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 27, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg276Gly (CGA>GGA): c.826 C>G in exon 5 of the EFHC1 gene (NM_018100.3). The Arg276Gly missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with a uncharged, non-polar Glycine residue. It alters a position in the DM10 domain of the protein that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, there have been no reported mutations in this region of the EFHC1 protein. Based on the currently available information, it is unclear whether Arg276Gly is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.;T;T;T;T;T;T;.;T;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.2	.;.;.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.3	.;.;.;D;.;.;.;.;.;.;.;.;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	.;.;.;D;.;.;.;.;.;.;.;.;D
Sift4G	Uncertain	0.0080	.;.;.;D;.;.;.;.;.;.;.;.;D
Polyphen		0.87	.;.;.;P;.;.;.;.;.;.;.;.;.
Vest4		0.71, 0.73
MutPred		0.54		.;.;.;Loss of stability (P = 0.0641);Loss of stability (P = 0.0641);Loss of stability (P = 0.0641);Loss of stability (P = 0.0641);Loss of stability (P = 0.0641);.;Loss of stability (P = 0.0641);.;.;.;
MVP		0.67
MPC		0.48
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.81
gMVP		0.79

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: rs796052414; hg19: chr6-52318995;