6-52492310-A-T

Variant names:

• chr6-52492310-A-T
• rs574948354
• NM_018100.4:c.1892A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018100.4(EFHC1):​c.1892A>T​(p.Tyr631Phe) 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. Y631C) 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: 4.17
• Publications: 1 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

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.1892A>T	p.Tyr631Phe	missense	Exon 11 of 11	NP_060570.2
	EFHC1	NM_001172420.2		c.1835A>T	p.Tyr612Phe	missense	Exon 12 of 12	NP_001165891.1
	EFHC1	NR_033327.2		n.3218A>T		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHC1	ENST00000371068.11	TSL:1 MANE Select	c.1892A>T	p.Tyr631Phe	missense	Exon 11 of 11	ENSP00000360107.4
	EFHC1	ENST00000637340.1	TSL:1	n.3817A>T		non_coding_transcript_exon	Exon 10 of 10
	EFHC1	ENST00000636702.1	TSL:5	c.1862A>T	p.Tyr621Phe	missense	Exon 12 of 12	ENSP00000489623.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0087	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.78		Gain of MoRF binding (P = 0.0689)
MVP		0.63
MPC		0.20
ClinPred		0.91	D
GERP RS		4.7
Varity_R		0.34
gMVP		0.15
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs574948354; hg19: chr6-52357108;