Genetic Variant CISD2:p.Glu4Glu (chr4-102869096-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7

The NM_001008388.5(CISD2):c.12G>A(p.Glu4Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,611,418 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00087 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

CISD2
NM_001008388.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.70

Publications

0 publications found

Variant links:

Genes affected

CISD2 (HGNC:24212): (CDGSH iron sulfur domain 2) The protein encoded by this gene is a zinc finger protein that localizes to the endoplasmic reticulum. The encoded protein binds an iron/sulfur cluster and may be involved in calcium homeostasis. Defects in this gene are a cause of Wolfram syndrome 2. [provided by RefSeq, Mar 2011]

CISD2 links:

UBE2D3 (HGNC:12476): (ubiquitin conjugating enzyme E2 D3) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. This enzyme functions in the ubiquitination of the tumor-suppressor protein p53, which is induced by an E3 ubiquitin-protein ligase. [provided by RefSeq, Jan 2017]

UBE2D3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 4-102869096-G-A is Benign according to our data. Variant chr4-102869096-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288522.

BP7

Synonymous conserved (PhyloP=1.7 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008388.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CISD2	NM_001008388.5	MANE Select	c.12G>A	p.Glu4Glu	synonymous	Exon 1 of 3	NP_001008389.1	Q8N5K1
UBE2D3	NM_181893.3		c.-352C>T		upstream_gene	N/A	NP_871622.1	P61077-3
UBE2D3	NM_181890.3		c.-510C>T		upstream_gene	N/A	NP_871619.1	P61077-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CISD2	ENST00000273986.10	TSL:1 MANE Select	c.12G>A	p.Glu4Glu	synonymous	Exon 1 of 3	ENSP00000273986.4	Q8N5K1
CISD2	ENST00000895599.1		c.12G>A	p.Glu4Glu	synonymous	Exon 1 of 3	ENSP00000565658.1
CISD2	ENST00000912010.1		c.12G>A	p.Glu4Glu	synonymous	Exon 1 of 3	ENSP00000582069.1

Frequencies

GnomAD3 genomes

AF:

0.000880

AC:

134

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000180

AC:

AN:

244294

AF XY:

0.000106

show subpopulations

Gnomad AFR exome

AF:

0.00260

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000994

AC:

145

AN:

1459064

Hom.:

Cov.:

AF XY:

0.0000827

AC XY:

AN XY:

725518

show subpopulations

African (AFR)

AF:

0.00374

AC:

125

AN:

33432

American (AMR)

AF:

0.000135

AC:

AN:

44518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

85470

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111034

Other (OTH)

AF:

0.000199

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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

AF:

0.000873

AC:

133

AN:

152354

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00305

AC:

127

AN:

41592

American (AMR)

AF:

0.000327

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000461

Hom.:

Bravo

AF:

0.00108

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CISD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

1.7

PromoterAI

-0.030

Neutral

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over