NM_018100.4:c.165C>A

Variant names:

• chr6-52424047-C-A
• rs928396576
• NM_018100.4:c.165C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018100.4(EFHC1):​c.165C>A​(p.Asn55Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0520
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18371376).

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.165C>A	p.Asn55Lys	missense	Exon 2 of 11	NP_060570.2
	EFHC1	NM_001172420.2		c.108C>A	p.Asn36Lys	missense	Exon 3 of 12	NP_001165891.1
	EFHC1	NR_033327.2		n.234C>A		non_coding_transcript_exon	Exon 2 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHC1	ENST00000371068.11	TSL:1 MANE Select	c.165C>A	p.Asn55Lys	missense	Exon 2 of 11	ENSP00000360107.4
	EFHC1	ENST00000637340.1	TSL:1	n.833C>A		non_coding_transcript_exon	Exon 2 of 10
	EFHC1	ENST00000637353.1	TSL:5	c.165C>A	p.Asn55Lys	missense	Exon 2 of 11	ENSP00000490441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.052
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.33	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.47		Gain of ubiquitination at N55 (P = 0.0077)
MVP		0.70
MPC		0.10
ClinPred		0.68	D
GERP RS		4.2
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.40
Mutation Taster		=68/32	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: rs928396576; hg19: chr6-52288845;