rs116134831

Positions:

• chr6-52469419-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000371068.11(EFHC1):​c.1224C>T​(p.Asp408=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,992 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (17 hom.)
• Consequence: EFHC1 ENST00000371068.11 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.468

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 6-52469419-C-T is Benign according to our data. Variant chr6-52469419-C-T is described in ClinVar as [Benign]. Clinvar id is 128961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.468 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00586 (892/152258) while in subpopulation AFR AF= 0.0192 (799/41546). AF 95% confidence interval is 0.0181. There are 8 homozygotes in gnomad4. There are 440 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 892 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHC1	NM_018100.4	c.1224C>T	p.Asp408=	synonymous_variant	7/11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2	c.1167C>T	p.Asp389=	synonymous_variant	8/12		NP_001165891.1
EFHC1	NR_033327.2	n.2550C>T		non_coding_transcript_exon_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11	c.1224C>T	p.Asp408=	synonymous_variant	7/11	1	NM_018100.4	ENSP00000360107	P1

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 884 AN: 152140 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.00202 AC: 507 AN: 251226 Hom.: 4 AF XY: 0.00201 AC XY: 273 AN XY: 135758

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00408

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00102 AC: 1490 AN: 1461734 Hom.: 17 Cov.: 30 AF XY: 0.00114 AC XY: 826 AN XY: 727170

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00471

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00586 AC: 892 AN: 152258 Hom.: 8 Cov.: 32 AF XY: 0.00591 AC XY: 440 AN XY: 74446

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00478

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.00230 Hom.: 3

Bravo AF: 0.00604

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Absence seizure;C1850778:Myoclonic epilepsy, juvenile, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	10
DANN	Benign	0.51

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: rs116134831; hg19: chr6-52334217;