dbSNP rs11812882: CISD1:c.238-4696T>C (chr10-58282865-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018464.5(CISD1):c.238-4696T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0605 in 152,224 control chromosomes in the GnomAD database, including 327 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.061 ( 327 hom., cov: 32)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

CISD1
NM_018464.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.204

Publications

9 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.085 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018464.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CISD1	NM_018464.5	MANE Select	c.238-4696T>C		intron	N/A	NP_060934.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CISD1	ENST00000333926.6	TSL:1 MANE Select	c.238-4696T>C	intron	N/A	ENSP00000363041.4
CISD1	ENST00000464703.5	TSL:5	n.429-4696T>C	intron	N/A
CISD1	ENST00000488388.2	TSL:5	n.259-34T>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0605

AC:

9197

AN:

152104

Hom.:

325

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0872

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0488

Gnomad ASJ

AF:

0.0346

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0287

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0608

Gnomad OTH

AF:

0.0632

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0605

AC:

9212

AN:

152222

Hom.:

327

Cov.:

AF XY:

0.0575

AC XY:

4279

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0873

AC:

3626

AN:

41518

American (AMR)

AF:

0.0486

AC:

743

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0346

AC:

120

AN:

3472

East Asian (EAS)

AF:

0.000773

AC:

AN:

5176

South Asian (SAS)

AF:

0.0214

AC:

103

AN:

4824

European-Finnish (FIN)

AF:

0.0287

AC:

305

AN:

10614

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0608

AC:

4138

AN:

68010

Other (OTH)

AF:

0.0625

AC:

132

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

453

906

1359

1812

2265

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0619

Hom.:

323

Bravo

AF:

0.0640

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.7

(source)

DANN

Benign

0.48

PhyloP100

-0.20

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over