rs137852780

Variant names:

• chr6-52454147-G-A
• rs137852780
• NM_018100.4:c.776G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018100.4(EFHC1):​c.776G>A​(p.Cys259Tyr) 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 risk factor (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 2.32
• Publications: 4 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 2 ACMG points.

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

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.776G>A	p.Cys259Tyr	missense	Exon 5 of 11	NP_060570.2	Q5JVL4-1
	EFHC1	NM_001172420.2		c.719G>A	p.Cys240Tyr	missense	Exon 6 of 12	NP_001165891.1	Q5JVL4-3
	EFHC1	NR_033327.2		n.2102G>A		non_coding_transcript_exon	Exon 4 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHC1	ENST00000371068.11	TSL:1 MANE Select	c.776G>A	p.Cys259Tyr	missense	Exon 5 of 11	ENSP00000360107.4	Q5JVL4-1
	EFHC1	ENST00000637340.1	TSL:1	n.2701G>A		non_coding_transcript_exon	Exon 4 of 10
	EFHC1	ENST00000637353.1	TSL:5	c.776G>A	p.Cys259Tyr	missense	Exon 5 of 11	ENSP00000490441.1	A0A1B0GVB0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Absence seizure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.79	N
PhyloP100		2.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.31
Sift	Benign	0.18	T
Sift4G	Benign	0.081	T
Polyphen		0.27	B
Vest4		0.15
MutPred		0.76		Loss of catalytic residue at T261 (P = 0.1845)
MVP		0.83
MPC		0.20
ClinPred		0.40	T
GERP RS		5.9
Varity_R		0.12
gMVP		0.48
Mutation Taster		=4/96	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: rs137852780; hg19: chr6-52318945;