rs115205076

chr6-52454258-G-Achr6-52454258-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_018100.4(EFHC1):c.887G>A(p.Arg296His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 1,614,096 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict 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. R296C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.73

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068689287).
• BP6: Variant 6-52454258-G-A is Benign according to our data. Variant chr6-52454258-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137192.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}. Variant chr6-52454258-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 441 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.887G>A	p.Arg296His	missense_variant	5/11	ENST00000371068.11
EFHC1	NM_001172420.2	c.830G>A	p.Arg277His	missense_variant	6/12
EFHC1	NR_033327.2	n.2213G>A		non_coding_transcript_exon_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.887G>A	p.Arg296His	missense_variant	5/11	1	NM_018100.4	P1

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 441 AN: 152128 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000780 AC: 196 AN: 251418 Hom.: 1 AF XY: 0.000574 AC XY: 78 AN XY: 135882

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000284 AC: 415 AN: 1461850 Hom.: 1 Cov.: 34 AF XY: 0.000223 AC XY: 162 AN XY: 727230

Gnomad4 AFR exome AF: 0.00944

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00294 AC: 447 AN: 152246 Hom.: 4 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74426

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000544 Hom.: 1

Bravo AF: 0.00322

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00101 AC: 123

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Juvenile myoclonic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.;T;T;T;T;T;T;.;T;.;.
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.0042
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D;D;.;D;D;D;D;D;D;D;D;.;D
MetaRNN	Benign	0.0069	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.33	T
Polyphen		0.067	.;.;.;B;.;.;.;.;.;.;.;.;.
Vest4		0.28, 0.27
MVP		0.73
MPC		0.13
ClinPred		0.033	T
GERP RS		4.1
Varity_R		0.18
gMVP		0.59

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: rs115205076; hg19: chr6-52319056;