Genetic Variant NM_025202.4:c.245C>G (chr2-232633949-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025202.4(EFHD1):c.245C>G(p.Thr82Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,445,314 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T82M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EFHD1
NM_025202.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.80

Publications

0 publications found

Variant links:

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]

EFHD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHD1	NM_025202.4 link	c.245C>G	p.Thr82Arg	missense_variant	Exon 1 of 4	ENST00000264059.8	NP_079478.1	Q9BUP0-1
EFHD1	NM_001308395.2 link	c.-171C>G		5_prime_UTR_variant	Exon 1 of 5		NP_001295324.1	Q9BUP0Q8WYH2
EFHD1	NM_001243252.2 link	c.14+27776C>G		intron_variant	Intron 1 of 3		NP_001230181.1	Q9BUP0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EFHD1	ENST00000264059.8 link	c.245C>G	p.Thr82Arg	missense_variant	Exon 1 of 4	1	NM_025202.4	ENSP00000264059.3	Q9BUP0-1
EFHD1	ENST00000409613.5 link	c.14+27776C>G		intron_variant	Intron 1 of 3	1		ENSP00000386556.1	Q9BUP0-2
EFHD1	ENST00000442845.1 link	n.233C>G		non_coding_transcript_exon_variant	Exon 1 of 5	3		ENSP00000395119.1	H7C0I0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445314

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719530

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39530

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111248

Other (OTH)

AF:

0.00

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.91

MetaRNN

Uncertain

0.67

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.2

PhyloP100

4.8

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

0.98

Vest4

0.46

MutPred

0.33

Gain of disorder (P = 0.0223);

MVP

0.81

MPC

0.30

ClinPred

1.0

GERP RS

2.6

PromoterAI

-0.036

Neutral

(source)

Varity_R

0.70

gMVP

0.89

Mutation Taster

=55/45

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over