Variant 10-58287597-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018464.5(CISD1):c.274G>A(p.Glu92Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,609,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CISD1
NM_018464.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.64

Variant links:

Genes affected

CISD1 (HGNC:30880): (CDGSH iron sulfur domain 1) This gene encodes a protein with a CDGSH iron-sulfur domain and has been shown to bind a redox-active [2Fe-2S] cluster. The encoded protein has been localized to the outer membrane of mitochondria and is thought to play a role in regulation of oxidation. Genes encoding similar proteins are located on chromosomes 4 and 17, and a pseudogene of this gene is located on chromosome 2. [provided by RefSeq, Feb 2012]

CISD1 links:

CISD1 (HGNC:):

CISD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14503151).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CISD1	NM_018464.5 linkuse as main transcript	c.274G>A	p.Glu92Lys	missense_variant	3/3	ENST00000333926.6	NP_060934.1	Q9NZ45A0A024QZN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CISD1	ENST00000333926.6 linkuse as main transcript	c.274G>A	p.Glu92Lys	missense_variant	3/3	1	NM_018464.5	ENSP00000363041.4	Q9NZ45
CISD1	ENST00000464703.5 linkuse as main transcript	n.465G>A		non_coding_transcript_exon_variant	4/5	5
CISD1	ENST00000488388.2 linkuse as main transcript	n.479G>A		non_coding_transcript_exon_variant	4/4	5
CISD1	ENST00000489785.5 linkuse as main transcript	n.342G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

247890

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133996

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1457934

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74220

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2024

The c.274G>A (p.E92K) alteration is located in exon 3 (coding exon 3) of the CISD1 gene. This alteration results from a G to A substitution at nucleotide position 274, causing the glutamic acid (E) at amino acid position 92 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

0.33

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.15

Eigen

Benign

-0.21

Eigen_PC

Benign

0.0083

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.0043

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.59

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.2

REVEL

Benign

0.037

Sift

Benign

0.29

Sift4G

Benign

0.47

Polyphen

0.032

Vest4

0.17

MutPred

0.29

Gain of ubiquitination at E92 (P = 0.0077);

MVP

0.21

MPC

0.44

ClinPred

0.34

GERP RS

4.2

Varity_R

0.34

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over