rs373196171

Variant names:

• chr6-52479127-C-T
• rs373196171
• NM_018100.4:c.1369C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_018100.4(EFHC1):​c.1369C>T​(p.Arg457Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (1 hom.)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.45

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a domain DM10 3 (size 104) in uniprot entity EFHC1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_018100.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.25755262).
• BS2: High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHC1	NM_018100.4	c.1369C>T	p.Arg457Cys	missense_variant	Exon 8 of 11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2	c.1312C>T	p.Arg438Cys	missense_variant	Exon 9 of 12		NP_001165891.1
EFHC1	NR_033327.2	n.2695C>T		non_coding_transcript_exon_variant	Exon 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11	c.1369C>T	p.Arg457Cys	missense_variant	Exon 8 of 11	1	NM_018100.4	ENSP00000360107.4

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000836 AC: 21 AN: 251324 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135828

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461842 Hom.: 1 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 727224

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74464

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 457 of the EFHC1 protein (p.Arg457Cys). This variant is present in population databases (rs373196171, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with EFHC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 411569). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. -

not provided Uncertain:1

Jun 14, 2021

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;.;T;T;T;T;T;T;.;T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.96	D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.0	.;.;.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.7	.;.;.;D;.;.;.;.;.;.;.;.;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.025	.;.;.;D;.;.;.;.;.;.;.;.;D
Sift4G	Uncertain	0.033	.;.;.;D;.;.;.;.;.;.;.;.;D
Polyphen		0.98	.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.50, 0.48
MVP		0.80
MPC		0.36
ClinPred		0.60	D
GERP RS		1.9
Varity_R		0.50
gMVP		0.71

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: rs373196171; hg19: chr6-52343925; COSMIC: COSV64136431; COSMIC: COSV64136431;