rs35648306

Variant names:

• chr6-52492311-C-T
• rs35648306
• NM_018100.4:c.1893C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018100.4(EFHC1):​c.1893C>T​(p.Tyr631Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,990 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (16 hom.)
• Consequence: EFHC1 NM_018100.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.500
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 6-52492311-C-T is Benign according to our data. Variant chr6-52492311-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0075 (1142/152308) while in subpopulation AFR AF = 0.0262 (1089/41566). AF 95% confidence interval is 0.0249. There are 16 homozygotes in GnomAd4. There are 562 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1142 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018100.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHC1	NM_018100.4	MANE Select	c.1893C>T	p.Tyr631Tyr	synonymous	Exon 11 of 11	NP_060570.2
	EFHC1	NM_001172420.2		c.1836C>T	p.Tyr612Tyr	synonymous	Exon 12 of 12	NP_001165891.1
	EFHC1	NR_033327.2		n.3219C>T		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHC1	ENST00000371068.11	TSL:1 MANE Select	c.1893C>T	p.Tyr631Tyr	synonymous	Exon 11 of 11	ENSP00000360107.4
	EFHC1	ENST00000637340.1	TSL:1	n.3818C>T		non_coding_transcript_exon	Exon 10 of 10
	EFHC1	ENST00000636702.1	TSL:5	c.1863C>T	p.Tyr621Tyr	synonymous	Exon 12 of 12	ENSP00000489623.1

Frequencies

GnomAD3 genomes AF: 0.00740 AC: 1126 AN: 152190 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00174 AC: 438 AN: 251218 AF XY: 0.00127

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000763 AC: 1115 AN: 1461682 Hom.: 16 Cov.: 32 AF XY: 0.000670 AC XY: 487 AN XY: 727150

African (AFR) AF: 0.0263 AC: 880 AN: 33458

American (AMR) AF: 0.00112 AC: 50 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111914

Other (OTH) AF: 0.00187 AC: 113 AN: 60378

GnomAD4 genome AF: 0.00750 AC: 1142 AN: 152308 Hom.: 16 Cov.: 32 AF XY: 0.00755 AC XY: 562 AN XY: 74470

African (AFR) AF: 0.0262 AC: 1089 AN: 41566

American (AMR) AF: 0.00216 AC: 33 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00287 Hom.: 4

Bravo AF: 0.00775

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Absence seizure;C1850778:Myoclonic epilepsy, juvenile, susceptibility to, 1 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.0
DANN	Benign	0.48
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs35648306; hg19: chr6-52357109;