rs115913738

Positions:

• chr6-52469350-C-A
• chr6-52469350-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018100.4(EFHC1):​c.1155C>A​(p.Asn385Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N385N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0900

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.1155C>A	p.Asn385Lys	missense_variant	7/11	ENST00000371068.11
EFHC1	NM_001172420.2	c.1098C>A	p.Asn366Lys	missense_variant	8/12
EFHC1	NR_033327.2	n.2481C>A		non_coding_transcript_exon_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.1155C>A	p.Asn385Lys	missense_variant	7/11	1	NM_018100.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461678 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727134

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	0.0030	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T;.;.;T;T;T;T;T;T;.;T;.;.
Eigen	Benign	-0.0031
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.97	D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.7	.;.;.;H;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.8	.;.;.;D;.;.;.;.;.;.;.;.;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	.;.;.;D;.;.;.;.;.;.;.;.;D
Sift4G	Uncertain	0.0060	.;.;.;D;.;.;.;.;.;.;.;.;D
Polyphen		1.0	.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.90, 0.88
MutPred		0.43		.;.;.;Gain of methylation at N385 (P = 0.0122);Gain of methylation at N385 (P = 0.0122);Gain of methylation at N385 (P = 0.0122);Gain of methylation at N385 (P = 0.0122);Gain of methylation at N385 (P = 0.0122);.;Gain of methylation at N385 (P = 0.0122);.;.;.;
MVP		0.80
MPC		0.50
ClinPred		0.99	D
GERP RS		-0.81
Varity_R		0.69
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs115913738; hg19: chr6-52334148;