chr6-52492310-A-T

Position:

• chr6-52492310-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_018100.4(EFHC1):​c.1892A>T​(p.Tyr631Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y631C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFHC1 NM_018100.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.17

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-52492310-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFHC1	NM_018100.4	c.1892A>T	p.Tyr631Phe	missense_variant	11/11	ENST00000371068.11
EFHC1	NM_001172420.2	c.1835A>T	p.Tyr612Phe	missense_variant	12/12
EFHC1	NR_033327.2	n.3218A>T		non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFHC1	ENST00000371068.11	c.1892A>T	p.Tyr631Phe	missense_variant	11/11	1	NM_018100.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;.;T;T;T;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;.;D;D;D;.;D
M_CAP	Benign	0.0087	T
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	.;.;M;.;.;.;.
MutationTaster	Benign	0.58	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	.;.;N;.;.;.;N
REVEL	Benign	0.22
Sift	Uncertain	0.0020	.;.;D;.;.;.;D
Sift4G	Uncertain	0.0060	.;.;D;.;.;.;D
Polyphen		1.0	.;.;D;.;.;.;.
Vest4		0.51, 0.43
MutPred		0.78		.;.;Gain of MoRF binding (P = 0.0689);.;.;.;.;
MVP		0.63
MPC		0.20
ClinPred		0.91	D
GERP RS		4.7
Varity_R		0.34
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs574948354; hg19: chr6-52357108;