chr2-232681657-G-A

Position:

• chr2-232681657-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025202.4(EFHD1):​c.658G>A​(p.Glu220Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFHD1 NM_025202.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.36

Genes affected

EFHD1 (HGNC:29556): (EF-hand domain family member D1) This gene encodes a member of the EF-hand super family of calcium binding proteins, which are involved in a variety of cellular processes including mitosis, synaptic transmission, and cytoskeletal rearrangement. The protein encoded by this gene is composed of an N-terminal disordered region, proline-rich elements, two EF-hands, and a C-terminal coiled-coil domain. This protein has been shown to associate with the mitochondrial inner membrane, and in HeLa cells, acts as a novel mitochondrial calcium ion sensor for mitochondrial flash activation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27825055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHD1	NM_025202.4	c.658G>A	p.Glu220Lys	missense_variant	4/4	ENST00000264059.8	NP_079478.1
EFHD1	NM_001243252.2	c.370G>A	p.Glu124Lys	missense_variant	4/4		NP_001230181.1
EFHD1	NM_001308395.2	c.322G>A	p.Glu108Lys	missense_variant	5/5		NP_001295324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHD1	ENST00000264059.8	c.658G>A	p.Glu220Lys	missense_variant	4/4	1	NM_025202.4	ENSP00000264059	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Ambry Genetics

Sep 25, 2023

The c.658G>A (p.E220K) alteration is located in exon 4 (coding exon 4) of the EFHD1 gene. This alteration results from a G to A substitution at nucleotide position 658, causing the glutamic acid (E) at amino acid position 220 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.040	.;T;T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;.;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.6	.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N;N;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.17	T;T;T;T;.
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.82	.;P;.;.;.
Vest4		0.53
MutPred		0.24		.;Gain of MoRF binding (P = 0.0043);.;.;.;
MVP		0.21
MPC		0.53
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.24
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-233546367;