4-102872502-T-C

Variant names:

• chr4-102872502-T-C
• rs223330
• NM_001008388.5:c.103+3315T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001008388.5(CISD2):​c.103+3315T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 152,016 control chromosomes in the GnomAD database, including 26,464 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 0.58 (26464 hom., cov: 32)
• Consequence: CISD2 NM_001008388.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.314
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• Wolfram syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Wolfram syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CISD2	NM_001008388.5	MANE Select	c.103+3315T>C		intron	N/A	NP_001008389.1	Q8N5K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CISD2	ENST00000273986.10	TSL:1 MANE Select	c.103+3315T>C		intron	N/A	ENSP00000273986.4	Q8N5K1
	CISD2	ENST00000503643.1	TSL:2	c.133+2990T>C		intron	N/A	ENSP00000423716.1	D6RCF4
	CISD2	ENST00000895599.1		c.103+3315T>C		intron	N/A	ENSP00000565658.1

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87381 AN: 151896 Hom.: 26415 Cov.: 32

Gnomad AFR AF: 0.776

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.586

Gnomad NFE AF: 0.481

Gnomad OTH AF: 0.583

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.576 AC: 87486 AN: 152016 Hom.: 26464 Cov.: 32 AF XY: 0.575 AC XY: 42721 AN XY: 74316

African (AFR) AF: 0.777 AC: 32194 AN: 41456

American (AMR) AF: 0.574 AC: 8766 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1858 AN: 3472

East Asian (EAS) AF: 0.521 AC: 2698 AN: 5174

South Asian (SAS) AF: 0.509 AC: 2451 AN: 4820

European-Finnish (FIN) AF: 0.465 AC: 4909 AN: 10548

Middle Eastern (MID) AF: 0.582 AC: 170 AN: 292

European-Non Finnish (NFE) AF: 0.481 AC: 32700 AN: 67958

Other (OTH) AF: 0.578 AC: 1218 AN: 2106

Alfa AF: 0.525 Hom.: 2533

Bravo AF: 0.593

Asia WGS AF: 0.527 AC: 1830 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	6.3
DANN	Benign	0.57
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs223330; hg19: chr4-103793659;