rs749929571

Positions:

• chr6-52464981-C-G
• chr6-52464981-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018100.4(EFHC1):​c.1003C>G​(p.Leu335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. L335R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.231

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047706366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.1003C>G	p.Leu335Val	missense_variant	6/11	ENST00000371068.11
EFHC1	NM_001172420.2	c.946C>G	p.Leu316Val	missense_variant	7/12
EFHC1	NR_033327.2	n.2329C>G		non_coding_transcript_exon_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.1003C>G	p.Leu335Val	missense_variant	6/11	1	NM_018100.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.6
DANN	Benign	0.081
DEOGEN2	Benign	0.0052	T;.;.;T;T;T;T;T;T;.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.035	N
LIST_S2	Uncertain	0.89	D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.048	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.60	.;.;.;N;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.1	.;.;.;N;.;.;.;.;.;.;.;.;N
REVEL	Benign	0.048
Sift	Benign	0.93	.;.;.;T;.;.;.;.;.;.;.;.;T
Sift4G	Benign	1.0	.;.;.;T;.;.;.;.;.;.;.;.;T
Polyphen		0.0060	.;.;.;B;.;.;.;.;.;.;.;.;.
Vest4		0.10, 0.11
MutPred		0.46		.;.;.;Loss of catalytic residue at L335 (P = 0.0447);Loss of catalytic residue at L335 (P = 0.0447);Loss of catalytic residue at L335 (P = 0.0447);Loss of catalytic residue at L335 (P = 0.0447);Loss of catalytic residue at L335 (P = 0.0447);.;Loss of catalytic residue at L335 (P = 0.0447);.;.;.;
MVP		0.55
MPC		0.086
ClinPred		0.051	T
GERP RS		-0.26
Varity_R		0.045
gMVP		0.34

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: rs749929571; hg19: chr6-52329779;