dbSNP rs137852778: EFHC1:p.Asp253Asn (chr6-52454128-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4BS2

The NM_018100.4(EFHC1):c.757G>A(p.Asp253Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D253Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

EFHC1
NM_018100.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.83

Publications

4 publications found

Variant links:

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]

EFHC1 Gene-Disease associations (from GenCC):

juvenile myoclonic epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

EFHC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28460014).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
EFHC1	NM_018100.4 link	c.757G>A	p.Asp253Asn	missense_variant	Exon 5 of 11	ENST00000371068.11	NP_060570.2
EFHC1	NM_001172420.2 link	c.700G>A	p.Asp234Asn	missense_variant	Exon 6 of 12		NP_001165891.1
EFHC1	NR_033327.2 link	n.2083G>A		non_coding_transcript_exon_variant	Exon 4 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFHC1	ENST00000371068.11 link	c.757G>A	p.Asp253Asn	missense_variant	Exon 5 of 11	1	NM_018100.4	ENSP00000360107.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000847

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Aug 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

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

0.077

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.061

T;.;.;T;T;T;T;T;T;.;T;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.029

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

D;D;.;D;D;D;D;D;D;D;D;.;D

M_CAP

Benign

0.050

MetaRNN

Benign

0.28

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.0

.;.;.;L;.;.;.;.;.;.;.;.;.

PhyloP100

2.8

PrimateAI

Benign

0.46

PROVEAN

Benign

0.0

.;.;.;D;.;.;.;.;.;.;.;.;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.;T;.;.;.;.;.;.;.;.;T

Sift4G

Pathogenic

0.0

.;.;.;T;.;.;.;.;.;.;.;.;T

Vest4

0.0

ClinPred

0.86

GERP RS

5.0

Varity_R

0.12

gMVP

0.32

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over