6-52423941-T-C

Position:

• chr6-52423941-T-C

Variant summary

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

The NM_018100.4(EFHC1):​c.64-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00084 in 1,613,990 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: EFHC1 NM_018100.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005603
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.163

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 (BayesDel_noAF=-0.63).
• BP6: Variant 6-52423941-T-C is Benign according to our data. Variant chr6-52423941-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137193.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}.
• BS2: High AC in GnomAd4 at 89 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.64-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000371068.11
EFHC1	NM_001172420.2	c.7-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
EFHC1	NR_033327.2	n.133-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.64-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_018100.4	P1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000868 AC: 218 AN: 251086 Hom.: 0 AF XY: 0.000891 AC XY: 121 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000867 AC: 1267 AN: 1461822 Hom.: 1 Cov.: 32 AF XY: 0.000887 AC XY: 645 AN XY: 727222

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00329

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.000933

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152168 Hom.: 1 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74340

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000923 Hom.: 0

Bravo AF: 0.000529

EpiCase AF: 0.000872

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2014	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. -

Juvenile myoclonic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.3
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000056
dbscSNV1_RF	Benign	0.0
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: rs201860746; hg19: chr6-52288739;