rs527295360

chr6-52465035-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_018100.4(EFHC1):c.1057C>T(p.Arg353Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R353Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.745

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0791612).
• BP6: Variant 6-52465035-C-T is Benign according to our data. Variant chr6-52465035-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205401.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.1057C>T	p.Arg353Trp	missense_variant	6/11	ENST00000371068.11
EFHC1	NM_001172420.2	c.1000C>T	p.Arg334Trp	missense_variant	7/12
EFHC1	NR_033327.2	n.2383C>T		non_coding_transcript_exon_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.1057C>T	p.Arg353Trp	missense_variant	6/11	1	NM_018100.4	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 251392 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000218 AC: 319 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.000217 AC XY: 158 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000684

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000208

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74380

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000177 Hom.: 0

Bravo AF: 0.000125

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 12, 2020	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 23, 2015

The R353W missense change was previously reported in three members of an Italian family, two of whom had classic juvenile myoclonic epilepsy and the other had idiopathic generalized epilepsy with grand mal tonic- clonic seizures (Annesi et al., 2007). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R353W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, it alters a poorly conserved position in the second DM10 domain of the EFHC1 gene and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The variant is found in EPILEPSY,CHILD-EPI panel(s). -

Seizure Benign:1

Benign, criteria provided, single submitter

research

Experimental Epileptology, AG Lerche, Hertie Institute for Clinical Brain Research

Jan 02, 2022

ACMG/AMP criteria: PP3, BP6, BS1, BS4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.075	T;.;.;T;T;T;T;T;T;.;T;.;.
Eigen	Benign	0.090
Eigen_PC	Benign	0.090
FATHMM_MKL	Benign	0.082	N
LIST_S2	Pathogenic	0.98	D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.079	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.21	T
Polyphen		0.84	.;.;.;P;.;.;.;.;.;.;.;.;.
Vest4		0.57, 0.71
MVP		0.87
MPC		0.19
ClinPred		0.13	T
GERP RS		3.5
Varity_R		0.11
gMVP		0.41

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: rs527295360; hg19: chr6-52329833;