rs1554261668

chr6-52479695-GGAGAGCAACGC-GTTTTGAAATACA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_018100.4(EFHC1):c.1549_1559delinsTTTTGAAATACA(p.Glu517PhefsTer2) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFHC1 NM_018100.4 stop_gained, frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.1549_1559delinsTTTTGAAATACA	p.Glu517PhefsTer2	stop_gained, frameshift_variant	9/11	ENST00000371068.11
EFHC1	NM_001172420.2	c.1492_1502delinsTTTTGAAATACA	p.Glu498PhefsTer2	stop_gained, frameshift_variant	10/12
EFHC1	NR_033327.2	n.2875_2885delinsTTTTGAAATACA		non_coding_transcript_exon_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.1549_1559delinsTTTTGAAATACA	p.Glu517PhefsTer2	stop_gained, frameshift_variant	9/11	1	NM_018100.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myoclonic epilepsy, juvenile, susceptibility to, 1;C5551411:Typical absence seizure Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 20, 2020

This sequence change creates a premature translational stop signal (p.Glu517Phefs*2) in the EFHC1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with EFHC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 534105). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in EFHC1 cause disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554261668; hg19: chr6-52344494;